Modulators of the glucocorticoid receptor and method

ABSTRACT

Novel non-steroidal compounds are provided which are glucocorticoid receptor modulators which are useful in treating diseases requiring glucocorticoid receptor agonist or antagonist therapy such as obesity, diabetes, inflammatory and immune disorders, and have the structure  
                 
 
     where Z is CONR 1 R 2  or CH 2 NR 1 R 2  and where R, R a , R b , R c , R d , Z, A and B are defined herein.

[0001] This application claims priority from U.S. ProvisionalApplication No. 60/396,877 filed Jul. 18, 2002 which is incorporatedherein by reference.

[0002] The present invention relates to new non-steroidal compoundswhich are glucocorticoid receptor (GR) modulators (that is agonists andantagonists) and thus are useful in treating diseases requiringglucocorticoid receptor agonist or antagonist therapy such as obesity,diabetes and inflammatory or immune associated diseases, and to a methodfor using such compounds to treat these and related diseases.

BACKGROUND OF THE INVENTION

[0003] The nuclear hormone receptor (NHR) family of transcriptionfactors bind low molecular weight ligands and either stimulate orrepress transcription (The Nuclear Receptor Facts Book, V. Laudet and H.Gronemeyer, Academic Press, p345, 2002). NHRs stimulate transcription bybinding to DNA and inducing transcription of specific genes. NHRs mayalso stimulate transcription by not binding to DNA itself, rather theymay modulate the activity of other DNA binding proteins (Stocklin, E.,et al., Nature (1996) 383:726-8). The process of stimulation oftranscription is called transactivation. NHRs repress transcription byinteracting with other transcription factors or coactivators andinhibiting the ability of these other transcription factors orcoactivators from inducing transcription of specific genes. Thisrepression is called transrepression. (for a review see The NuclearReceptor Factsbook, V. Laudet and H. Gronemeyer, Academic Press, p42,2002).

[0004] The glucocorticoid receptor (GR) is a member of the nuclearhormone receptor family of transcription factors, and a member of thesteroid hormone family of transcription factors. Affinity labeling ofthe glucocorticoid receptor protein allowed the production of antibodiesagainst the receptor which facilitated cloning the human (Weinberger, etal. Science 228, p640-742, 1985, Weinberger, et al. Nature, 318,p670-672, 1986) and rat (Miesfeld, R. Nature, 312, p779-781, 1985)glucocorticoid receptors.

[0005] Glucocorticoids which interact with GR have been used for over 50years to treat inflammatory diseases. It has been clearly shown thatglucocorticoids exert their anti-inflammatory activity via theinhibition by GR of the transcription factors NF-kappaB and AP-1. Thisinhibition is termed transrepression. It has been shown that the primarymechanism for inhibition of these transcription factors by GR is via adirect physical interaction. This interaction alters the transcriptionfactor complex and inhibits the ability of NF-kappaB and AP-1 tostimulate transcription (Jonat, C., et al. Cell, 62, p1189, 1990,Yang-Yen, H. F., et al. Cell 62, p1205, 1990, Diamond, M. I. et al.Science 249, p1266, 1990, Caldenhoven, E. et al., Mol. Endocrinol. 9,p401, 1995). Other mechanisms such as sequestration of co-activators byGR have also been proposed (Kamer Y, et al., Cell 85, p403, 1996,Chakravarti, D. et al., Nature 383, p99, 1996). NF-kappaB and AP-1 playkey roles in the initiation and perpetuation of inflammatory andimmunological disorders (Baldwin, AS, Journal of Clin. Investigation107, p3, 2001, Firestein, G. S., and Manning, A. M. Arthritis andRheumatism, 42, p609, 1999, Peltz, G., Curr. Opin, in Biotech. 8, p467,1997). NF-kappaB and AP-1 are involved in regulating the expression of anumber of important inflammatory and immunomodulatory genes including:TNF-alpha, IL-1, IL-2, IL-5, adhesion molecules (such as E-selectin),chemokines (such as Eoxtaxin and Rantes), Cox-2, and others.

[0006] In addition to causing transrepression, the interaction of aglucocorticoid with GR can cause GR to induce transcription of certaingenes. This induction of transcription is termed transactivation.Transactivation requires dimerization of GR and binding to aglucocorticoid response element (GRE).

[0007] Recent studies using a transgenic GR dimerization defective mousewhich cannot bind DNA have shown that the transactivation (DNA binding)activities of GR could be separated from the transrepressive (non-DNAbinding) effect of GR. These studies also indicate that many of the sideeffects of glucocorticoid therapy are due to the ability of GR to inducetranscription of various genes involved in metabolism, whereas,transrepression, which does not require DNA binding leads to suppressionof inflammation (Tuckermann, J. et al. Cell 93, p531, 1998; Reichardt,HM. EMBO J., 20, p7168, 2001).

[0008] The art is in need of modulators of NHRs. A modulator of an NHRmay be useful in treating NHR-associated diseases, that is diseasesassociated with the expression products of genes whose transcription isstimulated or repressed by NHRs. For instance, the art is in need ofmodulators of NHRs that inhibit AP-1 and NFκB, as such compounds wouldbe useful in the treatment of inflammatory and immune diseases anddisorders such as osteoarthritis, rheumatoid arthritis, multiplesclerosis, asthma, inflammatory bowel disease, transplant rejection andgraft vs. host disease.

[0009] Particularly concerning GR, although glucocorticoids are potentanti-inflammatory agents, their systemic use is limited by side effects.A compound that retained the anti-inflammatory efficacy ofglucocorticoids while minimizing the side effects such as diabetes,osteoporosis and glaucoma would be of great benefit to a very largenumber of patients with inflammatory diseases.

[0010] Additionally concerning GR, the art is in need of compounds thatantagonize transactivation. Such compounds may be useful in treatingmetabolic diseases associated with increased levels of glucocorticoid,such as diabetes, osteoporosis and glaucoma.

[0011] Additionally concerning GR, the art is in need of compounds thatcause transactivation. Such compounds may be useful in treatingmetabolic diseases associated with a deficiency in glucocorticoid. Suchdiseases include Addison's disease.

[0012] It is believed that the compounds of the present invention asdescribed below fill the above needs.

DESCRIPTION OF THE INVENTION

[0013] In accordance with the present invention, compounds are providedhaving the structure

[0014] including all stereoisomers thereof, or a prodrug ester thereof,or a pharmaceutically acceptable salt thereof, wherein

[0015] R is hydrogen, alkyl, alkenyl, alkynyl, alkoxy, aryl, arylalkyl,aryloxy, heteroaryl, cycloheteroalkyl, heteroarylalkyl,cycloheteroalkylalkyl, cycloalkyl, cycloalkylalkyl, cyanoalkyl,aminoalkyl, hydroxyalkyl, aryloxyalkyl, or hydroxyaryl;

[0016] R^(a) is hydrogen, alkyl, alkenyl, alkynyl, alkoxy, aryl,aryloxy, heteroaryl, cycloheteroalkyl, heteroarylalkyl,cycloheteroalkylalkyl, cyano, halogen, heteroarylaminocarbonyl,cycloheteroalkylcarbonyl, cyanoalkyl, alkylaminoalkyl, hydroxyalkyl,hydroxyaryl, aryloxyalkyl, nitro, amino, CHO, CO₂ alkyl, CONR^(e)R^(f),CH₂NR^(g)R^(h),CO₂H, CH₂OH, CH₂NHR^(g), NHCH₂R^(g), NHCHR^(g)R^(h),NHCOR^(e), NHCONR^(e)R^(f) or NHSO₂R^(e);

[0017] R^(b) is hydrogen, alkyl, alkenyl, alkynyl, alkoxy, aryl,aryloxy, heteroaryl, cycloheteroalkyl, heteroarylalkyl,cycloheteroalkylalkyl, cyano, halogen, heteroarylaminocarbonyl,cycloheteroalkylcarbonyl, cyanoalkyl, alkylaminoalkyl, hydroxyalkyl,nitro, amino, CHO, CO₂ alkyl, hydroxyaryl, aryloxyalkyl, CONR^(i)R^(j),CH₂NR^(k)R^(l), CO₂H, CH₂OH, CH₂NHR^(k), NHCH₂R^(k), NHCHR^(k)R^(l),NHCOR^(i), NHCONR^(i)R^(j) or NHSO₂R^(i);

[0018] where R^(e) and R^(f) are the same or different and areindependently selected from hydrogen, aryl, alkyl, alkenyl, alkynyl,alkoxy, amino, alkoxyalkyl, alkylaminoalkyl, dialkylaminoalkyl,heteroaryl, cycloheteroalkyl, heteroarylalkyl, cycloheteroalkylalkyl,cycloalkyl, or cycloalkylalkyl, and R^(e) and R^(f) can be takentogether with the nitrogen to which they are attached to form a 5-, 6-or 7-membered heteroaryl ring or cycloheteroalkyl ring which contains 1,2 or 3 hetero atoms which can be N, O or S;

[0019] R^(g) and R^(h) are the same or different and are independentlyselected from hydrogen, aryl, alkyl, alkenyl, alkynyl, alkoxy, amino,alkoxyalkyl, alkylaminoalkyl, dialkylaminoalkyl, heteroaryl,cycloheteroalkyl, heteroarylalkyl, cycloheteroalkylalkyl, cycloalkyl, orcycloalkylalkyl, and R^(g) and R^(h) can be taken together with thenitrogen to which they are attached to form a 5-, 6- or 7-memberedheteroaryl ring or cycloheteroalkyl ring which contains 1, 2 or 3 heteroatoms which can be N, O or S;

[0020] R^(i) and R^(j) are the same or different and are independentlyselected from hydrogen, aryl, alkyl, alkenyl, alkynyl, alkoxy, amino,alkoxyalkyl, alkylaminoalkyl, dialkylaminoalkyl, heteroaryl,cycloheteroalkyl, heteroarylalkyl, cycloheteroalkylalkyl, cycloalkyl, orcycloalkylalkyl, and R^(i) and R^(j) can be taken together with thenitrogen to which they are attached to form a 5-, 6- or 7-memberedheteroaryl ring or cycloheteroalkyl ring which contains 1, 2 or 3 heteroatoms which can be N, O or S;

[0021] R^(k) and R^(l) are the same or different and are independentlyselected from hydrogen, aryl, alkyl, alkenyl, alkynyl, alkoxy, amino,alkoxyalkyl, alkylaminoalkyl, dialkylaminoalkyl, heteroaryl,cycloheteroalkyl, heteroarylalkyl, cycloheteroalkylalkyl, cycloalkyl, orcycloalkylalkyl, and R^(k) and R^(l) can be taken together with thenitrogen to which they are attached to form a 5-, 6- or 7-memberedheteroaryl ring or cycloheteroalkyl ring which contains 1, 2 or 3 heteroatoms which can be N, O or S;

[0022] R^(c) and R^(d) are the same or different and are independentlyselected from hydrogen, alkyl, alkenyl, alkynyl, alkoxy, aryl, hydroxy,aryloxy, heteroaryl, cycloheteroalkyl, heteroarylalkyl,cycloheteroalkylalkyl, hydroxyaryl, or aryloxyalkyl;

[0023] R^(c) and R^(d) can be taken together with the carbon to whichthey are attached to form a 3- to 7-membered ring which may include an Oor N atom in the ring;

[0024] Z is CONR¹R² or CH₂NR¹R² wherein R¹ and R² are the same ordifferent and are independently selected from hydrogen, alkyl, alkenyl,alkynyl, alkoxy, cycloalkyl, cycloalkylalkyl, aryl, heteroaryl,heteroarylalkyl, cycloheteroalkyl, cycloalkenyl, mono- ordi-alkylaminoalkyl, cycloheteroalkylalkyl, hydroxyaryl, aryloxyalkyl,alkoxyalkyl or hydroxyalkyl;

[0025] the A ring represents a saturated, partially saturated orunsaturated 6-membered carbocyclic or heterocyclic ring; and

[0026] the B ring represents a saturated, partially saturated orunsaturated 6-membered carbocyclic or heterocyclic ring;

[0027] with the following provisos;

[0028] I. provided that where Z is CONR¹R² and (a) R is CH₃ or H andR^(a), R^(b), R^(c) and R^(d) are each hydrogen, or (b) R^(a) and R^(b)are each hydrogen and one of R^(c) and R^(d) is alkyl, then

[0029] (1) at least one of R¹ and R² is heteroaryl, heteroarylalkyl,cycloheteroalkyl or cycloheteroalkylalkyl, but where the heteroaryl is

[0030] then the other of R¹ and R² is other than hydrogen, and/or the Aring and/or the B ring includes a hetero atom; or

[0031] (2) where one of R¹ and R² is phenyl which is substituted withalkyl, hydroxy, halo, C₁-C₂-alkoxycarbonyl or nitro, then (a) the phenylmust be substituted with at least one other group other than hydrogen,alkyl, hydroxy, halo, C₁, —C₂-alkoxycarbonyl or nitro, except that thephenyl may be substituted with two or more halo atoms, and/or two ormore hydroxy groups, and/or (b) the other of R¹ and R² is other thanhydrogen and/or (c) the A ring and/or the B ring includes a hetero atom;

[0032] (3) where one of R¹ and R² is phenyl substituted with C₁-C₂alkoxy, the phenyl cannot be substituted with a second C₁-C₂ alkoxy orthe other of R¹ and R² is other than hydrogen, or

[0033] (4) where at least one of R¹ and R² is hydrogen, unsubstitutedalkyl, alkenyl, cycloalkyl, alkylcycloalkyl, cycloalkenyl,alkylcycloalkenyl, alkylphenyl, monoalkylaminoalkyl, dialkylaminoalkyl,arylalkyl, aryl, alkoxyalkyl or hydroxyalkyl then (a) the other of R¹and R² is other than hydrogen, unsubstituted alkyl, alkenyl, cycloaklyl,alkylcycloalkyl, cycloalkenyl, alkylcycloalkenyl, alkylphenyl,monoalkylaminoalkyl, dialkylaminoalkyl, arylalkyl, aryl, alkoxyalkyl orhydroxyalkyl; and/or (b) at least one of R^(a), R^(b), R^(c) and/orR^(d) is other than hydrogen and/or (c) R is other than hydrogen orC₁-C₂ alkyl and/or (d) the A ring and/or the B ring includes a heteroatom; and

[0034] II. provided that where Z is CH₂NR¹R² and/or where at least oneof R¹ and R² is hydrogen, alkyl, alkenyl, cycloalkyl, alkylcycloalkyl,phenyl, alkylphenyl, phenylalkyl, monoalkylaminoalkyl,dialkylaminoalkyl, arylalkyl, aryl, alkoxyalkyl, hydroxyalkyl,heteroaryl which is pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl orimidazolinyl, or cycloheteroalkyl which is 4,5-dihydro-imidazol-2-yl,piperidinyl or piperazinyl, then (a) the other of R¹ and R² is otherthan hydrogen, alkyl, alkenyl, cycloalkyl, alkylcycloalkyl, phenyl,alkylphenyl, phenylalkyl, monoalkylaminoalkyl, dialkylaminoalkyl,arylalkyl, aryl, alkoxyalkyl or hydroxyalkyl and/or (b) at least one ofR^(a), R^(b), R^(c) and/or R^(d) is other than hydrogen or C₁₋₂ alkyland/or (c) R is other than hydrogen or C₁-C₂ alkyl and/or (d) the A ringand/or the B ring includes a hetero atom and/or (e) one of R^(c) orR^(d) cannot be hydroxyalkyl.

[0035] In the compounds of formula I the A ring has the structure

[0036] and the B ring has the structure

[0037] wherein X₁, X₂, X₃ and X₄ are the same or different and areindependently selected from CH, CH₂, CHR¹⁵, CR¹⁵, CR¹⁶R¹⁷, N, NH, NR¹⁸,O or S, and X₅, X₆, X₇ and X₈ are the same or different and areindependently selected from CH, CH₂, CHR¹⁹, CR²⁰, CR²⁰R²¹, N, NH, NR²²,O or S, wherein R¹⁵, R¹⁶, R¹⁷, R¹⁸, R¹⁹, R²⁰, R²¹ and R²² are the sameor different and are independently selected from hydrogen, alkyl, aryl,cycloalkyl, heteroaryl, and cycloheteroalkyl, wherein each of said Aring and said B ring contains at most two nitrogen ring atoms, at mosttwo oxygen ring atoms and at most one sulfur ring atom.

[0038] It is preferred that the A ring and B ring are each 6-memberedrings which are aromatic carbocyclic rings, namely benzo rings, or areheterocyclic rings each of which includes one hetero atom, which isnitrogen, namely pyridyl rings preferably

[0039] Preferred compounds of formula I of the invention which haveglucocorticoid receptor (GR)/Dexamethasone (Dex) inhibition activity(>95% at 10 μM) are set out below:

[0040] 1. compounds of formula I of the invention where A and B arefused phenyl rings, R is CH³, R^(a), R^(b), R^(c) and R^(d) are each H,and Z is CONR¹R² where one of R¹ and R² is H and the other isheteroaryl, preferably imidazol-2-yl, that is

[0041] 2. compounds of formula I of the invention where A and B arefused phenyl rings, R is CH₃, R^(a), R^(b), R^(c) and R^(d) are each H,and Z is CONR¹R² where one of R¹ and R² is H and the other isheteroaryl, other than benzothiazol-2-yl, and preferably heteroaryl isalkylbenzothiazol-2-yl, alkoxybenzothiazol-2-yl, andhalobenzothiazol-2-yl, such as

[0042] 6-methylbenzothiazol-2-yl

[0043] 4-methoxybenzothiazol-2-yl

[0044] 6-fluorobenzothiazol-2-yl

[0045] 6-chlorobenzothiazol-2-yl

[0046] for example, compounds of the structure

[0047] where X is 6-CH₃, 4-CH₃O, 6-Cl or 6-F.

[0048] 3. compounds of formula I of the invention where A and B arefused phenyl rings, R is CH₃, R^(a), R^(b), R^(c) and R^(d)are each H,and Z is CONR¹R² where one of R¹ and R² is H and the other is a thiazolewhich preferably is substituted with dialkyl, alkyl,

[0049] alkyl, aryl such as phenyl or naphthyl (where the aryl may beoptionally substituted with halo, alkyl, nitro, hydroxy, alkoxy,dialkoxy, carboxy, alkylaminocarbonyl, arylaminocarbonyl,hydroxyalkylaminocarbonyl, cycloheteroalkylcarbonyl,alkoxyalkylaminocarbonyl, heteroarylaminocarbonyl), heteroarylthio orheteroaryl such as

[0050] 4,5-dimethylthiazol-2-yl

[0051] 5-chlorothiazol-2-yl

[0052] 4-methylthiazol-2-yl

[0053] 5-methylthiazol-2-yl

[0054] 4-phenylthiazol-2-yl

[0055] 4-(1-naphthyl)thiazol-2-yl

[0056] 5-(1-naphthyl)thiazol-2-yl

[0057] 4-[1-(4-fluoro)naphthyl]thiazol-2-yl

[0058] 4-[1-(4-methyl)naphthyl]thiazol-2-yl

[0059] 4-(3-nitrophenyl)thiazol-2-yl

[0060] 4-[1-(6-hydroxy)naphthyl]thiazol-2-yl

[0061] 4-[(1,2,4-triazol-5-yl)thio]methylthiazol-2-yl

[0062] 4-(4-benzoic acid)thiazol-2-yl

[0063] 4-[1-(4-bromo)naphthyl]thiazol-2-yl

[0064] 4-[4-N-ethylbenzamide]thiazol-2-yl

[0065] 4-[4-N-(2-methoxyphenyl)benzamide]thiazol-2-yl

[0066] 4-[4-N-methy-N-(2-hydroxyethyl)benzamide]thiazol-2-yl

[0067] 4-[4-N-(pyrrolidinyl)benzamide]thiazol-2-yl

[0068] 4-[4-N-(mopholinyl)benzamide]thiazol-2-yl

[0069] 4-[4-N-phenyl-N-methylbenzamide]thiazol-2-yl

[0070] 4-[3-N-ethylbenzamide]thiazol-2-yl

[0071] 4-[3-N-(2-methoxyphenyl)benzamide]thiazol-2-yl

[0072] 4-[3-N-(2-methoxyethyl)benzamide]thiazol-2-yl

[0073] 4-[3-N-methyl-N-2-hydroxyethyl)benzamide]thiazol-2-yl

[0074] 4-[3-N-methyl-N-phenylbenzamide]thiazol-2-yl

[0075] 4-[3-N-(4-acetylpiperaziny-1-yl)benzamide]thiazol-2-yl

[0076] 4-[3-N-(3-methoxypropyl)benzamide]thiazol-2-yl

[0077] 4-(6-carboxypyrid-2-yl)thiazol-2-yl

[0078] 4-[3-N-(3-hydroxy-4-methoxyphenyl)benzamide]thiazol-2-yl

[0079] 4-[3-N-(3-fluoro-4-methoxyphenyl)benzamide]thiazol-2-yl

[0080] 4-[3-N-(2,3-dimethoxyphenyl)benzamide]thiazol-2-yl

[0081] 4-[3-N-(3-dimethoxyphenyl)benzamide]thiazol-2-yl

[0082]4-[3-N-(5-trifluormethyl-1,3,4-thiadiazol-2-yl)benzamide]thiazol-2-yl

[0083] 4-[3-N-(5-methyl-1,3,4-thiadiazol-2-yl)benzamide]thiazol-2-yl

[0084] 4-[3-N-(5-chlorobenzoxazol-2-yl)benzamide]thiazol-2-yl

[0085] 4-[3-N-(3-benzonitrile)benzamide]thiazol-2-yl

[0086] 4-[3-N-(4-methoxypyrid-3-yl)benzamide]thiazol-2-yl

[0087] 4-[5-(1,4-benzodioxane)]thiazol-2-yl

[0088] 4-[4-(1,3-benzodioxole)]thiazol-2-yl,

[0089] for example, compounds of the structure

[0090] X=4,5-dimethyl, 5-chloro, 4-methyl, 5-methyl, 4-phenyl,4-(1-naphthyl), 4-(2-naphthyl), 4-(4-fluoronaphth-1-yl),4-(4-methylnaphth-1-yl), 4-(3-nitrophenyl), 4-(6-hydroxynaphth-1-yl),4-[(1,2,4-triazol-5-yl)thio]methyl, 4-benzoic acid,4-(4-bromonaphth-1-yl), 4-(N-ethyl)benzamide,4-(N-2-methoxyphenyl)benzamide, 4-(N-deoxyspergualinmethyl-N-2-hydroxyethyl)benzamide, 4-(N-(pyrrolidinyl)benzamide,4-(N-morpholinyl)benzamide,4-(N-phenyl-N-methyl)benzamide,3-(N-ethyl)benzamide, 3-(N-2-methoxyphenyl)benzamide,3-(N-2-methoxyethyl)benzamide, 3-(N-methyl-N-2-hydroxyethyl)benzamide,3-(N-methyl-N-phenyl)benzamide,3-(N-4-acetylpiperaziny-1-yl)benzamide,3-(N-3-methoxypropyl)benzamide, 2-(6-carboxy)pyridine,3-(N-3-hydroxy-4-methoxyphenyl)benzamide,3-(N-3-fluoro-4-methoxyphenyl)benzamide,3-(N-2,3-dimethoxyphenyl)benzamide, 3-(N-3-dimethoxyphenyl)benzamide,3-(N-5-trifluormethyl-1,3,4-thiadiazol-2-yl)benzamide,3-(N-5-methyl-1,3,4-thiadiazol-2-yl)benzamide,3-(N-5-chlorobenzoxazol-2-yl)benzamide, 3-(N-3-benzonitrile)benzamide,3-(N-4-methoxypyrid-3-yl)benzamide, 5-(1,4-benzodioxane),4-(1,3-benzodioxole).

[0091] 4. compounds of formula I of the invention where A and B arefused phenyl rings, R is C₂H₅, R^(a), R^(b), R^(c) and R^(d) are each H,and Z is CONR¹R² where one of R¹ and R² is H and the other isheteroaryl, preferably thiazol-2-yl or 4-(1-naphthyl)thiazol-2-yl.

[0092] 5. compounds of formula I of the invention where A and B arefused phenyl rings, R is 2-hydroxyethyl, R^(a), R^(b), R^(c) and R^(d)are each H, and Z is CONR¹R² where one of R¹ and R² is H and the otheris heteroaryl, preferably thiazol-2-yl.

[0093] 6. compounds of the formula I of the invention where A and B arefused phenyl rings, R is CH₃, R^(a), R^(b), R^(c) and R^(d) are H, and Zis CONR¹R² where one of R¹ and R² is H and the other is a heteroaryl,preferably 2-quinolin-1-yl.

[0094] Preferred compounds of formula I of the invention which have AP-1inhibitory activity (IC50<15 μM) are set out below:

[0095] 1(a). compounds of formula I of the invention where A and B arefused phenyl rings, R is CH₃, R^(a), R^(b), R^(c) and R^(d) are each H,and Z is CONR¹R² where one of R¹ and R² is H and the other isheteroaryl, preferably imidazole which is preferably substituted with anaryl group, which preferably is naphthyl preferably substituted withalkyl, halo or alkoxy, such as

[0096] 4-(1-naphthyl)imidazol-2-yl

[0097] 4-[1-(4-methyl)naphthyl]imidazol-2-yl

[0098] 4-[1-(4-fluoro)naphthyl]imidazol-2-yl

[0099] 4-[1-(6-methoxynaphthyl)]imidazol-2-yl

[0100] 4-phenylimidazol-2-yl

[0101] 4-t-butylimidazol-2-yl for example, compounds of the structure

[0102] X is aryl or alkyl, such as 1-naphthyl, 1-[(4-methyl)naphthyl,1-(4-fluoro)naphthyl, 1-(6-methoxynaphthyl), phenyl, t-butyl, orquinolinyl optionally substituted with alkyl such as methyl and/oralkoxy such as methoxy, or isoquinolinyl optionally substituted withalkyl such as methyl and/or alkoxy such as methoxy.

[0103] 1(b). Compounds of the Structure

R^(a) R^(b) X H H

H nitro

H H

H nitro

H H

H nitro

H H

H nitro

[0104] 2. compounds of formula I of the invention where A and B arefused phenyl rings, R is CH₃, R^(a), R^(b), R^(c) and R^(d) are each H,and Z is CONR¹R²

[0105] where one of R¹ and R² is H and the other is heteroaryl,preferably an oxazole which is preferably substituted with an aryl groupwhich preferably is naphthyl such as 4-(1-naphthyl)oxazol-2-yl,

[0106] that is, a compound of the structure

[0107] where X is aryl such as 1-naphthyl.

[0108] 3. compounds of formula I of the invention where A and B arefused phenyl rings, R is CH₃, R^(a), R^(b), R^(c) and R^(d) are each H,and Z is CONR¹R² where one of R¹ and R² is H and the other is a pyridylwhich is preferably substituted with an aryl group which preferably isnaphthyl, such as 4-(1-naphthyl)pyrid-2-yl, that is a compound of thestructure

[0109] where X is aryl such as 1-naphthyl.

[0110] 4. compounds of formula I of the invention where A and B arefused phenyl rings, R is CH₃, R^(a), R^(b), R^(c) and R^(d) are each H,and Z is CONR¹R² where one of R¹ and R² is H and the other is aheteroaryl, preferably a thiazole substituted with alkyl, aryl,heteroaryl or alkoxy, and where the aryl is phenyl, naphthyl oranthracenyl, which preferably is substituted with halo, alkyl alkoxy,aryl, or hydroxy, such as

[0111] 4-(phenyl)thiazol-2-yl

[0112] 4-(t-butyl)thiazol-2-yl

[0113] 4-(1-naphthyl)thiazol-2-yl

[0114] 4-[1-(4-fluoro)naphthyl]thiazol-2-yl

[0115] 4-(benzthiophen-3-yl)thiazol-2-yl

[0116] 4-[1-(4-methyl)naphthyl]thiazol-2-yl

[0117] 4-[-(2-methoxynaphthyl)]thiazol-2-yl

[0118] 4-[1-(6-methoxynaphthyl)]thiazol-2-yl

[0119] 4-(3-fluorophenyl)thiazol-2-yl

[0120] 4-(4-fluorophenyl)thiazol-2-yl

[0121] 4-(3-methylphenyl)thiazol-2-yl

[0122] 4-(2-chlorophenyl)thiazol-2-yl

[0123] 4-[1-(4-methoxynaphthyl)]thiazol-2-yl

[0124] 4-[1-(4-bromonaphthyl)]thiazol-2-yl

[0125] 4-[1-(4-iodonaphthyl)]thiazol-2-yl

[0126] 4-[anthracen-5-yl)]thiazol-2-yl

[0127] 4-[anthracen-1-yl)]thiazol-2-yl

[0128] 4-[4-quinolin-1-yl)]thiazol-2-yl

[0129] 4-[2-quinolin-1-yl)]thiazol-2-yl

[0130] 4-[1-(4-cyano-naphthyl)]thiazol-2-yl

[0131] 5-iodothiazol-2-yl

[0132] 4-(benzthiophen-4-yl)thiazol-2-yl

[0133] 4-[1-(2-hydroxynaphthyl)]thiazol-2-yl

[0134] 4-[1-(6-hydroxynaphthyl)]thiazol-2-yl

[0135] 4-[1-(4-hydroxynaphthyl)]thiazol-2-yl

[0136] for example, compounds of the structure

[0137] where X is aryl, alkyl, heteroaryl or halo, such as phenyl,t-butyl, 1-naphthyl, 1-(4-fluoro)naphthyl, benzthiophen-3-yl,1-(4-methyl)naphthyl, 1-(2-methoxy)naphthyl, 1-(6-methoxy)naphthyl,3-fluorophenyl, 4-fluorophenyl, 3-methylphenyl, 2-chlorophenyl,1-(4-methoxy)naphthyl, 1-(4-bromo)naphthyl, 1-(4-iodo)naphthyl,5-anthracenyl, 1-anthracenyl, 4-quinolin-1-yl, 2-quinolin-1-yl,1-(4-cyano)naphthyl, 5-iodo, 4-benzthiophenyl, 1-(2-hydroxy)naphthyl,1-(6-hydroxy)naphthyl, 1-(4-hydroxy)naphthyl.

[0138] 5. compounds of formula I of the invention where A and B arefused phenyl rings, R is C₂H₅, R^(a), R^(b), R^(c) and R^(d) are each H,and Z is CONR¹R² where one of R¹ and R² is H and the other is aheteroaryl, preferably thiazole which is substituted with aryl,preferably naphthyl, such as 4-(1-naphthyl)thiazol-2-yl, that is

[0139] 6. compounds of formula I of the invention where A and B arefused phenyl rings, R is CH₃, R^(a), R^(b), R^(c) and R^(d) are each H,and Z is CONR¹R² where one of R¹ and R² is H and the other is

[0140] that is

[0141] where X is aryl, alkoxyaryl, dialkoxyaryl, heteroaryl,heteroarylalkyl, halo (alkoxy)-aryl, hydroxy (alkoxy)aryl,trialkoxyaryl, alkyl(alkoxy)aryl, haloaryl, dihaloaryl, heteroarylaryl,alkylthioaryl, alkenylaryl, alkoxyheteroaryl, cyanoaryl, where aryl isphenyl or naphthyl and heteroaryl by itself or part of another group ispyridyl, imidazolyl, azido, isothiazolyl, pyrazolyl or thiadiazolyl;

[0142] preferred examples of X include

[0143] phenyl, 3-methoxyphenyl, 4-methoxyphenyl, 2,5-dimethoxyphenyl,3,5-dimethoxyphenyl, 3-pyridyl, 2-(4-pyridyl)ethyl,2-(4-imidazolyl)ethyl, 3-chloro-4-methoxyphenyl,3-hydroxy-4-methoxyphenyl, 3-fluoro-4-methoxyphenyl,3,4,5-trimethoxyphenyl, 3,4-dimethoxyphenyl, 4-methyl-3-methoxyphenyl,3-methoxyphenyl, 3,5-dimethoxyphenyl, 2,3-dimethoxyphenyl,4-chlorophenyl, 2-naphthyl, 3-chlorophenyl, 3,4-dichlorophenyl,4-azidophenyl, 2,4-dimethoxyphenyl, 3-ethoxyphenyl,3-(methylthio)phenyl, 4-(methylthio)phenyl, 3-(acetylenyl)phenyl,4-methoxy-3-pyridyl, 3-cyanophenyl, 2-methyl-4-methoxyphenyl,3-azidophenyl, 3-methyl-isothiazolyl, 1-methyl-pyrazol-5-yl or5-trifluormethyl-1,3,4-thiadiazol-2-yl.

[0144] 7. compounds of formula I of the invention of the structure (a)Ih

R^(a) R^(b) X carboxymethyl H H nitro H H cyano H H carboxymethyl Hmethyl nitro H methyl cyano H methyl H carboxymethyl H H nitro H H cyanoH H formyl H H CO—(N-morpholine) H H CH₂—NH—ethyl H H CH₂—(N-morpholine)H H nitro methyl H cyano methyl H NH₂ methyl H nitro F H cyano F H Cl HH Cl F H Cl Methyl H Br F H Br Methyl H CH3 H H CH3 F H CH3 Methyl (b)

(c)

Ii

[0145] Q═N, Y═CH or Q═CH, Y═N

[0146] Z═CONR¹R²

[0147] R═CH₃

[0148] R^(a),R^(b), R^(c), R^(d) are H

[0149] R=4-(4-fluoronaphthyl)thiazol-2-yl

[0150] R¹=H. (d)

R^(a) R^(b) X CH₃OOC— H H Nitro H H Cyano H H CH₃OOC— H Methyl Nitro HMethyl Cyano H Methyl H CH₃OOC— H H Nitro H H Cyano H H formyl H HCO—(N-morpholine) H H —CH2—NH—Ethyl H H —CH2—(N-morpholine) H H NitroMethyl H Cyano Methyl H NH2 Methyl H Nitro F H Cyano F H Cl H H Cl F HCl Methyl H Br F H Br Methyl H CH3 H H CH3 F H CH3 Methyl

[0151] 8. Compounds of Formula I of the Structure

[0152] wherein one of R¹ and R² is heteroaryl, preferably wherein one ofR¹ and R² is

[0153] where R^(m) is selected from H, alkyl, aryl, heteroaryl, halo, oralkoxy and R^(O) is H or alkyl, and more preferably where one of R¹ andR² is

[0154] Other preferred compounds of the invention have the structure

[0155] where R is CH₃, C₂H₅ or 2-hydroxyethy], Rb is H, CN, NO₂,halogen, alkyl or amino, and

[0156] Xb is H, arylalkoxycarbonyl, arylalkylaminocarbonyl,alkoxyalkylaminocarbonyl, heteroarylcarbonyl, aryl,alkoxyalkylamidocarbonyl, arylaminocarbonyl, heteroarylaminocarbonyl,arylaminocarbonylaryl or heteroaryl;

[0157] provided that where Xb is H, then R is C₂H₅ or 2-hydroxymethyl orRb is CN or NO₂.

[0158] Examples of the above preferred compounds include the following:

[0159] Still other preferred compounds of the invention have thestructure

[0160] where R is CH₃, C₂H₅ or 2-hydroxyethyl, Rb is H, CN, NO₂,halogen, alkyl or amino, and Xc is aryl, quinolinyl or isoquinolinyl.

[0161] Examples of the above preferred compounds include the following:

[0162] In another aspect of the present invention, there is providedpharmaceutical compositions useful in treating endocrine disorders,rheumatic disorders, collagen diseases, dermatologic disease, allergicdisease, ophthalmic disease, respiratory disease, hematologic disease,gastrointestinal disease, inflammatory disease, autoimmune disease,diabetes, obesity, and neoplastic disease, as well as other uses asdescribed herein, which includes a therapeutically effective amount(depending upon use) of a compound of formula I of the invention and apharmaceutically acceptable carrier.

[0163] In still another aspect, the present invention provides a methodof preventing, inhibiting onset of or treating endocrine disorders,rheumatic disorders, collagen diseases, dermatologic disease, allergicdisease, ophthalmic disease, respiratory disease, hematologic disease,gastrointestinal disease, inflammatory disease, autoimmune disease,diabetes, obesity, and neoplastic disease, GR-associated diseases, thatis a disease associated with the expression product of a gene whosetranscription is stimulated or repressed by GR or a disease associatedwith GR transactivation, including inflammatory and immune diseases anddisorders as described hereinafter, which includes the step ofadministering a therapeutically effective amount of a compound offormula I of the invention to a patient in need of treatment.

[0164] Another aspect of the present involves a method for preventing,inhibiting onset of or treating a disease associated with AP-1-dependentgene expression, that is a disease associated with the expression of agene under the regulatory control of AP-1, such as inflammatory andimmune disorders, cancer and tumor disorders, such as solid tumors,lymphomas and leukemia, and fungal infections such as mycosis fungoides.

[0165] The term “disease associated with GR transactivation,” as usedherein, refers to a disease associated with the transcription product ofa gene whose transcription is transactivated by a GR. Such diseasesinclude, but are not limited to: osteoporosis, diabetes, glaucoma,muscle loss, facial swelling, personality changes, hypertension,obesity, depression, and AIDS, the condition of wound healing, primaryor secondary andrenocortical insufficiency, and Addison's disease.

[0166] The term “treat”, “treating”, or “treatment,” in all grammaticalforms, as used herein refers to the prevention, reduction, oramelioration, partial or complete alleviation, or cure of a disease,disorder, or condition.

[0167] The terms “glucocorticoid receptor” and “GR,” as used herein,refer either to a member of the nuclear hormone receptor family oftranscription factors which bind glucocorticoids and either stimulate orrepress transcription, or to GR-beta. These terms, as used herein, referto glucocorticoid receptor from any source, including but not limitedto: human glucocorticoid receptor as disclosed in Weinberger, et al.Science 228, p640-742, 1985, and in Weinberger, et al. Nature, 318,p670-672, 1986; rat glucocorticoid receptor as disclosed in Miesfeld, R.Nature, 312, p779-781, 1985; mouse glucocortoid receptor as disclosed inDanielson, M. et al. EMBO J., 5, 2513; sheep glucocorticoid receptor asdisclosed in Yang, K., et al. J. Mol. Endocrinol. 8, p173-180, 1992;marmoset glucocortoid receptor as disclosed in Brandon, D. D., et al, J.Mol. Endocrinol. 7, p89-96, 1991; and human GR-beta as disclosed inHollenberg, SM. et al. Nature, 318, p635, 1985, Bamberger, C. M. et al.J. Clin Invest. 95, p2435, 1995.

[0168] The term, “disease associated with AP-1-dependent geneexpression,” as used herein, refers to a disease associated with theexpression product of a gene under the regulatory control of AP-1. Suchdiseases include, but are not limited to: inflammatory and immunediseases and disorders; cancer and tumor disorders, such as solidtumors, lymphomas and leukemia; and fungal infections such as mycosisfungoides.

[0169] The term “inflammatory or immune associated diseases ordisorders” is used herein to encompass any condition, disease, ordisorder that has an inflammatory or immune component, including, butnot limited to, each of the following conditions: transplant rejection(e.g., kidney, liver, heart, lung, pancreas (e.g., islet cells), bonemarrow, cornea, small bowel, skin allografts, skin homografts (such asemployed in burn treatment), heart valve xenografts, serum sickness, andgraft vs. host disease, autoimmune diseases, such as rheumatoidarthritis, psoriatic arthritis, multiple sclerosis, Type I and Type IIdiabetes, juvenile diabetes, obesity, asthma, inflammatory bowel disease(such as Crohn's disease and ulcerative colitis), pyoderma gangrenum,lupus (systemic lupus erythematosis), myasthenia gravis, psoriasis,dermatitis, dermatomyositis; eczema, seborrhoea, pulmonary inflammation,eye uveitis, hepatitis, Grave's disease, Hashimoto's thyroiditis,autoimmune thyroiditis, Behcet's or Sjorgen's syndrome (dry eyes/mouth),pernicious or immunohaemolytic anaemia, atherosclerosis, Addison'sdisease (autoimmune disease of the adrenal glands), idiopathic adrenalinsufficiency, autoimmune polyglandular disease (also known asautoimmune polyglandular syndrome), glomerulonephritis, scleroderma,morphea, lichen planus, viteligo (depigmentation of the skin), alopeciaareata, autoimmune alopecia, autoimmune hypopituatarism, Guillain-Barresyndrome, and alveolitis; T-cell mediated hypersensitivity diseases,including contact hypersensitivity, delayed-type hypersensitivity,contact dermatitis (including that due to poison ivy), uticaria, skinallergies, respiratory allergies (hayfever, allergic rhinitis) andgluten-sensitive enteropathy (Celiac disease); inflammatory diseasessuch as osteoarthritis, acute pancreatitis, chronic pancreatitis, acuterespiratory distress syndrome, Sezary's syndrome and vascular diseaseswhich have an inflammatory and or a proliferatory component such asrestenosis, stenosis and artherosclerosis. Inflammatory or immuneassociated diseases or disorders also includes, but is not limited to:endocrine disorders, rheumatic disorders, collagen diseases,dermatologic disease, allergic disease, ophthalmic disease, respiratorydisease, hematologic disease, gastrointestinal disease, inflammatorydisease, autoimmune disease, congenital adrenal hyperplasia,nonsuppurative thyroiditis, hypercalcemia associated with cancer,juvenile rheumatoid arthritis, Ankylosing spondylitis, acute andsubacute bursitis, acute nonspecific tenosynovitis, acute goutyarthritis, post-traumatic osteoarthritis, synovitis of osteoarthritis,epicondylitis, acute rheumatic carditis, pemphigus, bullous dermatitisherpetiformis, severe erythema multiforme, exfoliative dermatitis,seborrheic dermatitis, seasonal or perennial allergic rhinitis,bronchial asthma, contact dermatitis, atopic dermatitis, drughypersensitivity reactions, allergic conjunctivitis, keratitis, herpeszoster ophthalmicus, iritis and iridocyclitis, chorioretinitis, opticneuritis, symptomatic sarcoidosis, fulminating or disseminated pulmonarytuberculosis chemotherapy, idiopathic thrombocytopenic purpura inadults, secondary thrombocytopenia in adults, acquired (autoimmune)hemolytic anemia, leukemias and lymphomas in adults, acute leukemia ofchildhood, regional enteritis, autoimmune vasculitis, multiplesclerosis, chronic obstructive pulmonary disease, solid organ transplantrejection, sepsis.

[0170] In addition, in accordance with the present invention a method oftreating a disease associated with AP-1-induced or NFκB-inducedtranscription is provided wherein a compound of formula I of theinvention is administered to a patient in need of treatment in atherapeutically effective amount to induce NHR transrepression of theAP-1-induced or NFκB-induced transcription, thereby treating thedisease.

[0171] Other therapeutic agents, such as those described hereafter, maybe employed with the compounds of the invention in the present methods.In the methods of the present invention, such other therapeutic agent(s)may be administered prior to, simultaneously with or following theadministration of the compound(s) of the present invention.

[0172] In a particular embodiment, the compounds of the presentinvention are useful for the treatment of the aforementioned exemplarydisorders irrespective of their etiology, for example, for the treatmentof transplant rejection, rheumatoid arthritis, inflammatory boweldisease, and viral infections.

Methods of Preparation

[0173] The compounds of the present invention may be synthesized by manymethods available to those skilled in the art of organic chemistry.General synthetic schemes, in accordance with the present invention, forpreparing compounds of the present invention are described below. Theseschemes are illustrative and are not meant to limit the possibletechniques one skilled in the art may use to prepare the compoundsdisclosed herein. Different methods to prepare the compounds of thepresent invention will be evident to those skilled in the art.Additionally, the various steps in the synthesis may be performed in analternate sequence in order to give the desired compound or compounds.Examples of compounds of the present invention prepared by methodsdescribed in the general schemes are given in the preparations andexamples section set out hereinafter.

Compounds of Formula I

[0174] Compounds of formula I of the invention are prepared as describedin the Schemes and examples below. In the schemes the various groups A,B, Z, R, R^(a), R^(b), R^(c), and R^(d) correspond to those describedabove.

[0175] General methods for the synthesis of compounds of the inventionof structure IA of the invention where A and B are each fused phenyl orpyridyl, and Z is

[0176] are well known in the literature. Compound IA is constructed bythe cycloaddition of a compound of formula 1 with an unsaturatedcompound of formula 2 neat or in an appropriate solvent such as xylenesor benzene, at temperatures ranging from 50 to 200° C. to form compound3 (which is a novel intermediate). It is well known that thecycloaddition may be facilitated by the use of a catalysts suchdiethylaluminium chloride or boron trifluoride diethyl etherate. Thecycloaddition may also be carried out at higher pressures as when thereactions are performed in sealed vessels.

[0177] Compound 3 is reacted with an amine of formula 4 by one of themany methods of amidation well known to those skilled in the art(preferably treatment of 3 in a suitable solvent such as acetonitrilewith diethylaminoethyl chloride hydrochloride (DEC),1-hydroxy-7-azabenzotriazole, triethylamine and amine 4) to providecompounds of the invention of structure IA.

[0178] The starting compound 1 is known in the art and may becommercially available or prepared employing procedures known in theart.

Scheme B

[0179] Compounds of formula I of the invention where R is other than Hand Z is

[0180] (that is IA) may be prepared preferably starting with compound 3where R is H which is treated with a suitable base such as lithiumdiisopropylamide (LDA) in a suitable solvent such as tetrahydrofuran ordethyl ether and at a temperature ranging from −100° C. to 100° C. andwith a compound 5 (R^(x)-LG, where LG is a leaving group, such as methyliodide and R^(x) is R other than H) affords compounds of structure 6.Compound 6 may be subjected to amidation as described in Scheme A toform compounds of the invention IA (where R is other than H).

[0181] Compounds of formula I of the invention where Z is

[0182] where each of R¹ and R² is other than H may be prepared startingwith compound of formula IA where R^(1a) is R¹ other than H and R² is Hwhich is treated with base such as sodium hydride and compound 5aR^(2a)-LG, where LG is a leaving group, such as methyl iodide, andR^(2a) is R² other than H, to provide compounds of structure IB of theinvention where R¹ and R² are other than H.

[0183] Compounds of formula I of the invention where Z is —CH₂NR¹R²(that is IC) may be prepared starting with compounds of formula IA whichwhen treated with a reducing agent such as lithium aluminum hydride(LAH) provides compounds IC of the invention.

[0184] Compounds of formula I of the invention where one or more of A,B, Z, R, R^(a), R^(b), R^(c) and R^(d) includes a hydroxyaryl group maybe prepared as follows.

[0185] A compound of formula IA of the invention that contains one ormore aryloxyalkyl groups located in A, B, Z, R, R^(a), R^(b), R^(c), andR^(d) when treated with dealkylating agent such as boron tribromide,sodium methyl sulfide or other known dealkylating agents providesphenols of formula ID of the invention.

[0186] A compound of formula IE where R^(a) or R^(b) is a functionalgroup such as CHO, NH₂, CO₂H or NO₂ may be further elaborated by variousmethods well known to those skilled in the art to give compounds ofstructure IF. A few illustrative examples are shown below. The newlyintroduced groups may also be further elaborated,

[0187] The following compounds are new intermediates and may be preparedemploying procedures set out hereinbefore and/or known in the art:

[0188] or an alkyl ester thereof,

[0189] where R is CH₃, C₂H₅; R^(a) is nitro, cyano, Cl, Br, CH3,—COOCH3, formyl and R^(b) is H; R^(b) is nitro, cyano, Cl, Br, CH3,—COOCH3, formyl and R^(a) is H; and

[0190] where X₉ is S or NH; X is:

Definition of Terms

[0191] Unless otherwise indicated, the term “lower alkyl”, “alkyl” or“alk” as employed herein alone or as part of another group includes bothstraight and branched chain hydrocarbons, containing 1 to 20 carbons,preferably 1 to 10 carbons, more preferably 1 to 8 carbons, in thenormal chain, and may optionally include an oxygen or nitrogen in thenormal chain, such as methyl, ethyl, propyl, isopropyl, butyl, t-butyl,isobutyl, pentyl, hexyl, isohexyl, heptyl, 4,4-dimethylpentyl, octyl,2,2,4-trimethylpentyl, nonyl, decyl, undecyl, dodecyl, the variousbranched chain isomers thereof, and the like as well as such groupsincluding 1 to 4 substituents such as halo, for example F, Br, Cl or Ior CF₃, alkoxy, aryl, aryloxy, aryl(aryl) or diaryl, arylalkyl,arylalkyloxy, alkenyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkyloxy,amino, hydroxy, hydroxyalkyl, acyl, heteroaryl, heteroaryloxy, HO—N═,cycloheteroalkyl, alkyloxycarbonyl, alkoxyoximyl, arylheteroaryl,arylalkoxycarbonyl, heteroarylalkyl, heteroarylalkoxy, aryloxyalkyl,aryloxyaryl, alkylamido, alkanoylamino, hydroxyalkyl (alkyl)aminocarbonyl, arylcarbonylamino, nitro, cyano, thiol, haloalkyl,trihaloalkyl and/or alkylthio and/or any of the substituents for aryl.

[0192] Unless otherwise indicated, the term “cycloalkyl” as employedherein alone or as part of another group includes saturated or partiallyunsaturated (containing 1 or 2 double bonds) cyclic hydrocarbon groupscontaining 1 to 3 rings, including monocyclicalkyl, bicyclicalkyl andtricyclicalkyl, containing a total of 3 to 20 carbons forming the rings,preferably 3 to 10 carbons, forming the ring and which may be fused to 1or 2 aromatic rings as described for aryl, which include cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclodecyland cyclododecyl, cyclohexenyl,

[0193] any of which groups may be optionally substituted with 1 to 4substituents such as halogen, alkyl, alkoxy, hydroxy, aryl, aryloxy,arylalkyl, cycloalkyl, alkylamido, alkanoylamino, oxo, acyl,arylcarbonylamino, amino, nitro, cyano, thiol and/or alkylthio and/orany of the substituents for alkyl.

[0194] The term “cycloalkenyl” as employed herein alone or as part ofanother group refers to cyclic hydrocarbons containing 3 to 12 carbons,preferably 5 to 10 carbons and 1 or 2 double bonds. Exemplarycycloalkenyl groups include cyclopentenyl, cyclohexenyl, cycloheptenyl,cyclooctenyl, cyclohexadienyl, and cycloheptadienyl, which may beoptionally substituted as defined for cycloalkyl.

[0195] The term “cycloalkylene” as employed herein refers to a“cycloalkyl” group which includes free bonds and thus is a linking groupsuch as

[0196] and the like, and may optionally be substituted as defined abovefor “cycloalkyl”.

[0197] The term “alkanoyl” as used herein alone or as part of anothergroup refers to alkyl linked to a carbonyl group.

[0198] Unless otherwise indicated, the term “lower alkenyl” or “alkenyl”as used herein by itself or as part of another group refers to straightor branched chain radicals of 2 to 20 carbons, preferably 2 to 12carbons, and more preferably 1 to 8 carbons in the normal chain, whichinclude one to six double bonds in the normal chain, and may optionallyinclude an oxygen or nitrogen in the normal chain, such as vinyl,2-propenyl, 3-butenyl, 2-butenyl, 4-pentenyl, 3-pentenyl, 2-hexenyl,3-hexenyl, 2-heptenyl, 3-heptenyl, 4-heptenyl, 3-octenyl, 3-nonenyl,4-decenyl, 3-undecenyl, 4-dodecenyl, 4,8,12-tetradecatrienyl, and thelike, and which may be optionally substituted with 1 to 4 substituents,namely, halogen, haloalkyl, alkyl, alkoxy, alkenyl, alkynyl, aryl,arylalkyl, cycloalkyl, amino, hydroxy, heteroaryl, cycloheteroalkyl,alkanoylamino, alkylamido, arylcarbonylamino, nitro, cyano, thiol,alkylthio and/or any of the substituents for alkyl set out herein.

[0199] Unless otherwise indicated, the term “lower alkynyl” or “alkynyl”as used herein by itself or as part of another group refers to straightor branched chain radicals of 2 to 20 carbons, preferably 2 to 12carbons and more preferably 2 to 8 carbons in the normal chain, whichinclude one triple bond in the normal chain, and may optionally includean oxygen or nitrogen in the normal chain, such as 2-propynyl,3-butynyl, 2-butynyl, 4-pentynyl, 3-pentynyl, 2-hexynyl, 3-hexynyl,2-heptynyl, 3-heptynyl, 4-heptynyl, 3-octynyl, 3-nonynyl,4-decynyl,3-undecynyl, 4-dodecynyl and the like, and which may beoptionally substituted with 1 to 4 substituents, namely, halogen,haloalkyl, alkyl, alkoxy, alkenyl, alkynyl, aryl, arylalkyl, cycloalkyl,amino, heteroaryl, cycloheteroalkyl, hydroxy, alkanoylamino, alkylamido,arylcarbonylamino, nitro, cyano, thiol, and/or alkylthio, and/or any ofthe substituents for alkyl set out herein.

[0200] The terms “arylalkenyl” and “arylalkynyl” as used alone or aspart of another group refer to alkenyl and alkynyl groups as describedabove having an aryl substituent.

[0201] Where alkyl groups as defined above have single bonds forattachment to other groups at two different carbon atoms, they aretermed “alkylene” groups and may optionally be substituted as definedabove for “alkyl”.

[0202] Where alkenyl groups as defined above and alkynyl groups asdefined above, respectively, have single bonds for attachment at twodifferent carbon atoms, they are termed “alkenylene groups” and“alkynylene groups”, respectively, and may optionally be substituted asdefined above for “alkenyl” and “alkynyl”.

[0203] (CH₂)_(p) and (CH₂)_(q), includes alkylene, allenyl, alkenyleneor alkynylene groups, as defined herein, each of which may optionallyinclude an oxygen or nitrogen in the normal chain, which may optionallyinclude 1, 2, or 3 substituents which include alkyl, alkenyl, halogen,cyano, hydroxy, alkoxy, amino, thioalkyl, keto, C₃-C₆ cycloalkyl,alkylcarbonylamino or alkylcarbonyloxy; the alkyl substituent may be analkylene moiety of 1 to 4 carbons which may be attached to one or twocarbons in the (CH₂)_(p) or (CH₂)_(q) group to form a cycloalkyl grouptherewith.

[0204] Examples of (CH₂)_(p), (CH₂)_(q), alkylene, alkenylene andalkynylene include

[0205] The term “halogen” or “halo” as used herein alone or as part ofanother group refers to chlorine, bromine, fluorine, and iodine as wellas CF₃, with chlorine or fluorine being preferred.

[0206] The term “metal ion” refers to alkali metal ions such as sodium,potassium or lithium and alkaline earth metal ions such as magnesium andcalcium, as well as zinc and aluminum.

[0207] Unless otherwise indicated, the term “aryl”, as employed hereinalone or as part of another group refers to monocyclic and bicyclicaromatic groups containing 6 to 10 carbons in the ring portion (such asphenyl or naphthyl including 1-naphthyl and 2-naphthyl) and mayoptionally include one to three additional rings fused to a carbocyclicring or a heterocyclic ring (such as aryl, cycloalkyl, heteroaryl orcycloheteroalkyl rings for example

[0208] and may be optionally substituted through available carbon atomswith 1, 2, or 3 groups selected from hydrogen, halo, haloalkyl, alkyl,haloalkyl, alkoxy, haloalkoxy, alkenyl, trifluoromethyl,trifluoromethoxy, alkynyl, cycloalkyl-alkyl, cycloheteroalkyl,cycloheteroalkylalkyl, aryl, heteroaryl, arylalkyl, aryloxy,aryloxyalkyl, arylalkoxy, alkoxycarbonyl, arylcarbonyl, arylalkenyl,aminocarbonylaryl, arylthio, arylsulfinyl, arylazo, heteroarylalkyl,heteroarylalkenyl, heteroarylheteroaryl, heteroaryloxy, hydroxy, nitro,cyano, amino, substituted amino wherein the amino includes 1 or 2substituents (which are alkyl, aryl or any of the other aryl compoundsmentioned in the definitions), thiol, alkylthio, arylthio,heteroarylthio, arylthioalkyl, alkoxyarylthio, alkylcarbonyl,arylcarbonyl, alkylaminocarbonyl, arylaminocarbonyl, alkoxycarbonyl,aminocarbonyl, alkylcarbonyloxy, arylcarbonyloxy, alkylcarbonylamino,arylcarbonylamino, arylsulfinyl, arylsulfinylalkyl, arylsulfonylamino orarylsulfonaminocarbonyl, carboxy, cycloalkyl, arylalkoxy,aryloxycarbonyl, cycloalkylaminocarbonyl, cycloalkylalkylaminocarbonyl,alkoxycarbonylalkyl, alkoxyalkylaminocarbonyl, heteroarylaminocarbonyl,heteroarylalkylaminocarbonyl, arylalkylaminocarbonyl,N-hydroxyalkyl(N-alkyl)aminocarbonyl, cycloheteroalkylaminocarbonyl,cycloheteroalkylalkylaminocarbonyl, N-aryl(N-alkyl)aminocarbonyl,N-arylalkyl(N-cyanoalkyl)aminocarbonyl, dialkylaminoalkylaminocarbonyl,dialkylaminocarbonyl, alkyl-, arylalkyl- oraryl-cycloheteroalkylaminocarbonyl, N-dialkylaminoalkyl(N-alkyl orN-arylalkyl)aminocarbonyl, N-heteroarylalkyl(N-alkyl)aminocarbonyl,N-arylalkyl(N-alkyl)aminocarbonyl,N-dialkylamino(N-arylalkyl)aminocarbonyl,N-hydroxyalkyl(N-arylalkyl)aminocarbonyl, aminoalkyloxycarbonyl,cycloheteroalkylcarbonyl, N═N═N, alkylsulfonyl, aminosulfonyl,heteroarylaminosulfonyl, and/or any of the substituents for alkyl setout herein.

[0209] Unless otherwise indicated, the term “lower alkoxy”, “alkoxy”,“aryloxy” or “aralkoxy” as employed herein alone or as part of anothergroup includes any of the above alkyl, aralkyl or aryl groups linked toan oxygen atom.

[0210] Unless otherwise indicated, the term “substituted amino” asemployed herein alone or as part of another group refers to aminosubstituted with one or two substituents, which may be the same ordifferent, such as alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl,cycloheteroalkyl, cycloheteroalkylalkyl, cycloalkyl, cycloalkylalkyl,haloalkyl, hydroxyalkyl, alkoxyalkyl or thioalkyl. These substituentsmay be further substituted with a carboxylic acid and/or any of thesubstituents for alkyl as set out above. In addition, the aminosubstituents may be taken together with the nitrogen atom to which theyare attached to form 1-pyrrolidinyl, 1-piperidinyl, 1-azepinyl,4-morpholinyl, 4-thiamorpholinyl, 1-piperazinyl, 4-alkyl-1-piperazinyl,4-arylalkyl-1-piperazinyl, 4-diarylalkyl-1-piperazinyl, 1-pyrrolidinyl,1-piperidinyl, or 1-azepinyl, optionally substituted with alkyl, alkoxy,alkylthio, halo, trifluoromethyl or hydroxy.

[0211] Unless otherwise indicated, the term “lower alkylthio”,alkylthio”, “arylthio” or “aralkylthio” as employed herein alone or aspart of another group includes any of the above alkyl, aralkyl or arylgroups linked to a sulfur atom.

[0212] Unless otherwise indicated, the term “lower alkylamino”,“alkylamino”, “arylamino”, or “arylalkylamino” as employed herein aloneor as part of another group includes any of the above alkyl, aryl orarylalkyl groups linked to a nitrogen atom.

[0213] Unless otherwise indicated, the term “acyl” as employed herein byitself or part of another group, as defined herein, refers to an organicradical linked to a carbonyl

[0214] group; examples of acyl groups include any of the R groupsattached to a carbonyl, such as alkanoyl, alkenoyl, aroyl, aralkanoyl,heteroaroyl, cycloalkanoyl, cycloheteroalkanoyl and the like.

[0215] Unless otherwise indicated, the term “cycloheteroalkyl” as usedherein alone or as part of another group refers to a 5-, 6- or7-membered saturated or partially unsaturated ring which includes 1 to 2hetero atoms such as nitrogen, oxygen and/or sulfur, linked through acarbon atom or a heteroatom, where possible, optionally via the linker(CH₂)_(p) (where p is 0, 1, 2 or 3), such as

[0216] and the like. The above groups may include 1 to 4 substituentssuch as alkyl, halo, oxo and/or any of of the substituents for alkyl oraryl set out herein. In addition, any of the cycloheteroalkyl rings canbe fused to a cycloalkyl, aryl, heteroaryl or cycloheteroalkyl ring.

[0217] Unless otherwise indicated, the term “heteroaryl” as used hereinalone or as part of another group refers to a 5-, 6- or 7-memberedaromatic ring which includes 1, 2, 3 or 4 hetero atoms such as nitrogen,oxygen or sulfur, and such rings fused to an aryl, cycloalkyl,heteroaryl or cycloheteroalkyl ring (e.g. benzothiophenyl, indolyl), andincludes possible N-oxides, linked through a carbon atom or aheteroatom, where possible, optionally via the linker (CH₂)_(q) (where qis 0, 1, 2 or 3). The heteroaryl group may optionally include 1 to 4substituents such as any of the substituents for alkyl or aryl set outabove. Examples of heteroaryl groups include the following:

[0218] and the like.

[0219] Examples of A rings and B rings include, but are not limited toany of the 6-membered heteroaryl groups as defined above, 6-memberedcycloheteroalkyl groups as defined above, and 6-membered aryl groups asdefined above.

[0220] The term “cycloheteroalkylalkyl” as used herein alone or as partof another group refers to cycloheteroalkyl groups as defined abovelinked through a C atom or heteroatom to a (CH₂)_(p) chain.

[0221] The term “heteroarylalkyl” or “heteroarylalkenyl” as used hereinalone or as part of another group refers to a heteroaryl group asdefined above linked through a C atom or heteroatom to a —(CH₂)_(q)—chain, alkylene or alkenylene as defined above.

[0222] The term “polyhaloalkyl” as used herein refers to an “alkyl”group as defined above which includes from 2 to 9, preferably from 2 to5, halo substituents, such as F or Cl, preferably F, such as CF₃CH₂, CF₃or CF₃CF₂CH₂.

[0223] The term “polyhaloalkyloxy” as used herein refers to an “alkoxy”or “alkyloxy” group as defined above which includes from 2 to 9,preferably from 2 to 5, halo substituents, such as F or Cl, preferablyF, such as CF₃CH₂O, CF₃O or CF₃CF₂CH₂O.

[0224] The term “prodrug esters” as employed herein includes prodrugesters which are known in the art for carboxylic and phosphorus acidesters such as methyl, ethyl, benzyl and the like. Other prodrug esterexamples include the following groups: (1-alkanoyloxy)alkyl such as,

[0225] wherein R^(Z), R^(t) and R^(Y) are H, alkyl, aryl or arylalkyl;however, R^(Z)O cannot be HO.

[0226] Examples of such prodrug esters include

[0227] Other examples of suitable prodrug esters include

[0228] wherein R^(Z) can be H, alkyl (such as methyl or t-butyl),arylalkyl (such as benzyl) or aryl (such as phenyl); R^(V) is H, alkyl,halogen or alkoxy, R^(u) is alkyl, aryl, arylalkyl or alkoxyl, and n₁ is0, 1 or 2.

[0229] The terms pharmaceutically acceptable “salt” and “salts” refer tobasic salts formed with inorganic and organic bases. Such salts includeammonium salts; alkali metal salts, such as lithium, sodium andpotassium salts (which are preferred); alkaline earth metal salts, suchas calcium and magnesium salts; salts with organic bases, such as aminelike salts (e.g., dicyclohexylamine salt, benzathine,N-methyl-D-glucamine, and hydrabamine salts); and salts with amino acidslike arginine, lysine and the like; and zwitterions, the so-called“inner salts”. Nontoxic, pharmaceutically acceptable salts arepreferred, although other salts are also useful, e.g., in isolating orpurifying the product.

[0230] The term pharmaceutically acceptable “salt” and “salts” alsoincludes acid addition salts. These are formed, for example, with stronginorganic acids, such as mineral acids, for example sulfuric acid,phosphoric acid or a hydrohalic acid such as HCl or HBr, with strongorganic carboxylic acids, such as alkanecarboxylic acids of 1 to 4carbon atoms which are unsubstituted or substituted, for example, byhalogen, for example acetic acid, such as saturated or unsaturateddicarboxylic acids, for example oxalic, malonic, succinic, maleic,fumaric, phthalic or terephthalic acid, such as hydroxycarboxylic acids,for example ascorbic, glycolic, lactic, malic, tartaric or citric acid,such as amino acids, (for example aspartic or glutamic acid or lysine orarginine), or benzoic acid, or with organic sulfonic acids, such as(C1-C4) alkyl or arylsulfonic acids which are unsubstituted orsubstituted, for example by halogen, for example methanesulfonic acid orp-toluenesulfonic acid.

[0231] All stereoisomers of the compounds of the instant invention arecontemplated, either in admixture or in pure or substantially pure form.The compounds of the present invention can have asymmetric centers atany of the carbon atoms including any one or the R substituents.Consequently, compounds of formula I can exist in enantiomeric ordiastereomeric forms or in mixtures thereof. The processes forpreparation can utilize racemates, enantiomers or diastereomers asstarting materials. When diastereomeric or enantiomeric products areprepared, they can be separated by conventional methods for example,chromatographic or fractional crystallization.

Combinations

[0232] Where desired, the compounds of structure I may be used incombination with one or more other types of therapeutic agents such asimmunosuppressants, anticancer agents, anti-viral agents,anti-inflammatory agents, anti-fungal agents, antibiotics, anti-vascularhyperproliferation agents, anti-depressive agents, hypolipidemic agentsor lipid-lowering agents or lipid modulating agents, antidiabeticagents, anti-obesity agents, antihypertensive agents, plateletaggregation inhibitors, and/or anti-osteoporosis agents, which may beadministered orally in the same dosage form, in a separate oral dosageform or by injection.

[0233] The immunosuppressants which may be optionally employed incombination with compounds of formula I of the invention includecyclosporins, for example cyclosporin A, mycophenolate, interferon-beta,deoxyspergolin, FK-506 or Ant.-IL-2.

[0234] The anti-cancer agents which may be optionally employed incombination with compounds of formula I of the invention includeazathiprine, 5-fluorouracil, cyclophosphamide, cisplatin, methotrexate,thiotepa, carboplatin, and the like.

[0235] The anti-viral agents which may be optionally employed incombination with compounds of formula I of the invention includeabacavir, aciclovir, ganciclovir, zidanocin, vidarabine, and the like.

[0236] The anti-inflammatory agents which may be optionally employed incombination with compounds of formula I of the invention includenon-steroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen, cox-2inhibitors such as celecoxib, rofecoxib, aspirin, naproxen, ketoprofen,diclofenac sodium, indomethacin, piroxicam, steroids such as prednisone,dexamethasone, hydrocortisone, triamcinolone diacetate, gold compounds,such as gold sodium thiomalate, TNF-α inhibitors such as tenidap,anti-TNF antibodies or soluble TNF receptor, and rapamycin (sirolimus orRapamune) or derivatives thereof, infliximab (Remicade® Centocor, Inc.).CTLA-4Ig, LEA29Y, antibodies such as anti-ICAM-3, anti-IL-2 receptor(Anti-Tac), anti-CD45RB, anti-CD2, anti-CD3 (OKT-3), anti-CD4,anti-CD80, anti-CD86, monoclonal antibody OKT3, agents blocking theinteraction between CD40 and CD154 (a.k.a. “gp39”), such as antibodiesspecific for CD40 and/or CD154, fusion proteins such as etanercept,fusion proteins constructed from CD40 and/or CD154gp39 (e.g. CD40Ig andCD8gp39), inhibitors, such as nuclear translocation inhibitors, ofNF-kappa B function, such as deoxyspergualin (DSG).

[0237] The anti-fungal agents which may be optionally employed incombination with compounds of formula I of the invention includefluconazole, miconazole, amphotericin B, and the like.

[0238] The antibiotics which may be optionally employed in combinationwith compounds of formula I of the invention include penicillin,tetracycline, amoxicillin, ampicillin, erythromycin, doxycycline,vancomycin, minocycline, clindamycin or cefalexin.

[0239] The anti-vascular hyperproliferation agents which may beoptionally employed with compounds of formula I of the invention includemethotrexate, leflunomide, FK506 (tacrolimus, Prograf),

[0240] The hypolipidemic agent or lipid-lowering agent or lipidmodulating agents which may be optionally employed in combination withthe compounds of formula I of the invention may include 1,2,3 or moreMTP inhibitors, HMG CoA reductase inhibitors, squalene synthetaseinhibitors, fibric acid derivatives, ACAT inhibitors, lipoxygenaseinhibitors, cholesterol absorption inhibitors, ileal Na⁺/bile acidcotransporter inhibitors, upregulators of LDL receptor activity, bileacid sequestrants, and/or nicotinic acid and derivatives thereof.

[0241] MTP inhibitors employed herein include MTP inhibitors disclosedin U.S. Pat. No. 5,595,872, U.S. Pat. No. 5,739,135, U.S. Pat. No.5,712,279, U.S. Pat. No. 5,760,246, U.S. Pat. No. 5,827,875, U.S. Pat.No. 5,885,983 and U.S. application Ser. No. 09/175,180 filed Oct. 20,1998, now U.S. Pat. No. 5,962,440. Preferred are each of the preferredMTP inhibitors disclosed in each of the above patents and applications.

[0242] All of the above U.S. Patents and applications are incorporatedherein by reference.

[0243] Most preferred MTP inhibitors to be employed in accordance withthe present invention include preferred MTP inhibitors as set out inU.S. Pat. Nos. 5,739,135 and 5,712,279, and U.S. Pat. No. 5,760,246.

[0244] The most preferred MTP inhibitor is9-[4-[4-[[2-(2,2,2-trifluoroethoxy)benzoyl]amino]-1-piperidinyl]butyl]-N-(2,2,2-trifluoroethyl)-9H-fluorene-9-carboxamide

[0245] The hypolipidemic agent may be an HMG CoA reductase inhibitorwhich includes, but is not limited to, mevastatin and related compoundsas disclosed in U.S. Pat. No. 3,983,140, lovastatin (mevinolin) andrelated compounds as disclosed in U.S. Pat. No. 4,231,938, pravastatinand related compounds such as disclosed in U.S. Pat. No. 4,346,227,simvastatin and related compounds as disclosed in U.S. Pat. Nos.4,448,784 and 4,450,171. Other HMG CoA reductase inhibitors which may beemployed herein include, but are not limited to, fluvastatin, disclosedin U.S. Pat. No. 5,354,772, cerivastatin disclosed in U.S. Pat. Nos.5,006,530 and 5,177,080, atorvastatin disclosed in U.S. Pat. Nos.4,681,893, 5,273,995, 5,385,929 and 5,686,104, itavastatin(Nissan/Sankyo's nisvastatin (NK-104)) disclosed in U.S. Pat. No.5,011,930, Shionogi-Astra/Zeneca visastatin (ZD-4522) disclosed in U.S.Pat. No. 5,260,440, and related statin compounds disclosed in U.S. Pat.No. 5,753,675, pyrazole analogs of mevalonolactone derivatives asdisclosed in U.S. Pat. No. 4,613,610, indene analogs of mevalonolactonederivatives as disclosed in PCT application WO 86/03488,6-[2-(substituted-pyrrol-1-yl)-alkyl)pyran-2-ones and derivativesthereof as disclosed in U.S. Pat. No. 4,647,576, Searle's SC-45355 (a3-substituted pentanedioic acid derivative) dichloroacetate, imidazoleanalogs of mevalonolactone as disclosed in PCT application WO 86/07054,3-carboxy-2-hydroxy-propane-phosphonic acid derivatives as disclosed inFrench Patent No. 2,596,393, 2,3-disubstituted pyrrole, furan andthiophene derivatives as disclosed in European Patent Application No.0221025, naphthyl analogs of mevalonolactone as disclosed in U.S. Pat.No. 4,686,237, octahydronaphthalenes such as disclosed in U.S. Pat. No.4,499,289, keto analogs of mevinolin (lovastatin) as disclosed inEuropean Patent Application No.0,142,146 A2, and quinoline and pyridinederivatives disclosed in U.S. Pat. Nos. 5,506,219 and 5,691,322.

[0246] In addition, phosphinic acid compounds useful in inhibiting HMGCoA reductase suitable for use herein are disclosed in GB 2205837.

[0247] The squalene synthetase inhibitors suitable for use hereininclude, but are not limited to, α-phosphono-sulfonates disclosed inU.S. Pat. No. 5,712,396, those disclosed by Biller et al, J. Med. Chem.,1988, Vol. 31, No. 10, pp 1869-1871, including isoprenoid(phosphinyl-methyl)phosphonates as well as other known squalenesynthetase inhibitors, for example, as disclosed in U.S. Pat. No.4,871,721 and 4,924,024 and in Biller, S. A., Neuenschwander, K.,Ponpipom, M. M., and Poulter, C. D., Current Pharmaceutical Design, 2,1-40 (1996).

[0248] In addition, other squalene synthetase inhibitors suitable foruse herein include the terpenoid pyrophosphates disclosed by P. Ortiz deMontellano et al, J. Med. Chem., 1977, 20, 243-249, the farnesyldiphosphate analog A and presqualene pyrophosphate (PSQ-PP) analogs asdisclosed by Corey and Volante, J. Am. Chem. Soc., 1976, 98, 1291-1293,phosphinylphosphonates reported by McClard, R. W. et al, J. A. C. S.,1987, 109, 5544 and cyclopropanes reported by Capson, T. L., PhDdissertation, June, 1987, Dept. Med. Chem. U of Utah, Abstract, Table ofContents, pp 16, 17, 40-43, 48-51, Summary.

[0249] Other hypolipidemic agents suitable for use herein include, butare not limited to, fibric acid derivatives, such as fenofibrate,gemfibrozil, clofibrate, bezafibrate, ciprofibrate, clinofibrate and thelike, probucol, and related compounds as disclosed in U.S. Pat. No.3,674,836, probucol and gemfibrozil being preferred, bile acidsequestrants such as cholestyramine, colestipol and DEAE-Sephadex(Secholex®, Policexide®) and cholestagel (Sankyo/Geltex), as well aslipostabil (Rhone-Poulenc), Eisai E-5050 (an N-substituted ethanolaminederivative), imanixil (HOE-402), tetrahydrolipstatin (THL),istigmastanylphos-phorylcholine (SPC, Roche), aminocyclodextrin (TanabeSeiyoku), Ajinomoto AJ-814 (azulene derivative), melinamide (Sumitomo),Sandoz 58-035, American Cyanamid CL-277,082 and CL-283,546(disubstituted urea derivatives), nicotinic acid (niacin), acipimox,acifran, neomycin, p-aminosalicylic acid, aspirin,poly(diallylmethylamine) derivatives such as disclosed in U.S. Pat. No.4,759,923, quaternary amine poly(diallyldimethylammonium chloride) andionenes such as disclosed in U.S. Pat. No. 4,027,009, and other knownserum cholesterol lowering agents.

[0250] The hypolipidemic agent may be an ACAT inhibitor such asdisclosed in, Drugs of the Future 24, 9-15 (1999), (Avasimibe); “TheACAT inhibitor, C1-1011 is effective in the prevention and regression ofaortic fatty streak area in hamsters”, Nicolosi et al, Atherosclerosis(Shannon, Irel). (1998), 137(1), 77-85; “The pharmacological profile ofFCE 27677: a novel ACAT inhibitor with potent hypolipidemic activitymediated by selective suppression of the hepatic secretion ofApoB100-containing lipoprotein”, Ghiselli, Giancarlo, Cardiovasc. DrugRev. (1998), 16(1), 16-30; “RP 73163: a bioavailablealkylsulfinyl-diphenylimidazole ACAT inhibitor”, Smith, C., et al,Bioorg. Med. Chem. Lett. (1996), 6(1), 47-50; “ACAT inhibitors:physiologic mechanisms for hypolipidemic and anti-atheroscleroticactivities in experimental animals”, Krause et al, Editor(s): Ruffolo,Robert R., Jr.; Hollinger, Mannfred A., Inflammation: Mediators Pathways(1995), 173-98, Publisher: CRC, Boca Raton, Fla.; “ACAT inhibitors:potential anti-atherosclerotic agents”, Sliskovic et al, Curr. Med.Chem. (1994), 1(3), 204-25; “Inhibitors of acyl-CoA:cholesterol O-acyltransferase (ACAT) as hypocholesterolemic agents. 6. The firstwater-soluble ACAT inhibitor with lipid-regulating activity. Inhibitorsof acyl-CoA:cholesterol acyltransferase (ACAT). 7. Development of aseries of substituted N-phenyl-N′-[(1-phenylcyclopentyl)methyl]ureaswith enhanced hypocholesterolemic activity”, Stout et al, Chemtracts:Org. Chem. (1995), 8(6), 359-62, or TS-962 (Taisho Pharmaceutical Co.Ltd).

[0251] The hypolipidemic agent may be an upregulator of LD2 receptoractivity such as MD-700 (Taisho Pharmaceutical Co. Ltd) and LY295427(Eli Lilly).

[0252] The hypolipidemic agent may be a cholesterol absorption inhibitorpreferably Schering-Plough's ezetimibe (SCH58235) and SCH48461 as wellas those disclosed in Atherosclerosis 115, 45-63 (1995) and J. Med.Chem. 41, 973 (1998).

[0253] The hypolipidemic agent may be an ileal Na⁺/bile acidcotransporter inhibitor such as disclosed in Drugs of the Future, 24,425-430 (1999).

[0254] The lipid-modulating agent may be a cholesteryl ester transferprotein (CETP) inhibitor such as Pfizer's CP 529,414 (WO/0038722 and EP818448) and Pharmacia's SC-744 and SC-795.

[0255] The ATP citrate lyase inhibitor which may be employed in thecombination of the invention may include, for example, those disclosedin U.S. Pat. No. 5,447,954.

[0256] Preferred hypolipidemic agents are pravastatin, lovastatin,simvastatin, atorvastatin, fluvastatin, cerivastatin, itavastatin andvisastatin and ZD-4522.

[0257] The above-mentioned U.S. patents are incorporated herein byreference. The amounts and dosages employed will be as indicated in thePhysician's Desk Reference and/or in the patents set out above.

[0258] The compounds of formula I of the invention will be employed in aweight ratio to the hypolipidemic agent (were present), within the rangefrom about 500:1 to about 1:500, preferably from about 100:1 to about1:100.

[0259] The dose administered must be carefully adjusted according toage, weight and condition of the patient, as well as the route ofadministration, dosage form and regimen and the desired result.

[0260] The dosages and formulations for the hypolipidemic agent will beas disclosed in the various patents and applications discussed above.

[0261] The dosages and formulations for the other hypolipidemic agent tobe employed, where applicable, will be as set out in the latest editionof the Physicians' Desk Reference.

[0262] For oral administration, a satisfactory result may be obtainedemploying the MTP inhibitor in an amount within the range of from about0.01 mg to about 500 mg and preferably from about 0.1 mg to about 100mg, one to four times daily.

[0263] A preferred oral dosage form, such as tablets or capsules, willcontain the MTP inhibitor in an amount of from about 1 to about 500 mg,preferably from about 2 to about 400 mg, and more preferably from about5 to about 250 mg, one to four times daily.

[0264] For oral administration, a satisfactory result may be obtainedemploying an HMG CoA reductase inhibitor, for example, pravastatin,lovastatin, simvastatin, atorvastatin, fluvastatin or cerivastatin indosages employed as indicated in the Physician's Desk Reference, such asin an amount within the range of from about 1 to 2000 mg, and preferablyfrom about 4 to about 200 mg.

[0265] The squalene synthetase inhibitor may be employed in dosages inan amount within the range of from about 10 mg to about 2000 mg andpreferably from about 25 mg to about 200 mg.

[0266] A preferred oral dosage form, such as tablets or capsules, willcontain the HMG CoA reductase inhibitor in an amount from about 0.1 toabout 100 mg, preferably from about 0.5 to about 80 mg, and morepreferably from about 1 to about 40 mg.

[0267] A preferred oral dosage form, such as tablets or capsules willcontain the squalene synthetase inhibitor in an amount of from about 10to about 500 mg, preferably from about 25 to about 200 mg.

[0268] The hypolipidemic agent may also be a lipoxygenase inhibitorincluding a 15-lipoxygenase (15-LO) inhibitor such as benzimidazolederivatives as disclosed in WO 97/12615, 15-LO inhibitors as disclosedin WO 97/12613, isothiazolones as disclosed in WO 96/38144, and 15-LOinhibitors as disclosed by Sendobry et al “Attenuation of diet-inducedatherosclerosis in rabbits with a highly selective 15-lipoxygenaseinhibitor lacking significant antioxidant properties”, Brit. J.Pharmacology (1997) 120, 1199-1206, and Cornicelli et al,“15-Lipoxygenase and its Inhibition: A Novel Therapeutic Target forVascular Disease”, Current Pharmaceutical Design, 1999, 5, 11-20.

[0269] The compounds of formula I and the hypolipidemic agent may beemployed together in the same oral dosage form or in separate oraldosage forms taken at the same time.

[0270] The compositions described above may be administered in thedosage forms as described above in single or divided doses of one tofour times daily. It may be advisable to start a patient on a low dosecombination and work up gradually to a high dose combination.

[0271] The preferred hypolipidemic agent is pravastatin, simvastatin,lovastatin, atorvastatin, fluvastatin or cerivastatin as well as niacinand/or cholestagel.

[0272] The other antidiabetic agent which may be optionally employed incombination with the compound of formula I may be 1,2,3 or moreantidiabetic agents or antihyperglycemic agents including insulinsecretagogues or insulin sensitizers, or other antidiabetic agentspreferably having a mechanism of action different from the compounds offormula I of the invention, which may include biguanides, sulfonylureas, glucosidase inhibitors, PPAR γ agonists, such asthiazolidinediones, aP2 inhibitors, dipeptidyl peptidase IV (DP4)inhibitors, SGLT2 inhibitors, and/or meglitinides, as well as insulin,and/or glucagon-like peptide-1 (GLP-1).

[0273] The other antidiabetic agent may be an oral antihyperglycemicagent preferably a biguanide such as metformin or phenformin or saltsthereof, preferably metformin HCl.

[0274] Where the antidiabetic agent is a biguanide, the compounds ofstructure I will be employed in a weight ratio to biguanide within therange from about 0.001:1 to about 10:1, preferably from about 0.01:1 toabout 5:1.

[0275] The other antidiabetic agent may also preferably be a sulfonylurea such as glyburide (also known as glibenclamide), glimepiride(disclosed in U.S. Pat. No. 4,379,785), glipizide, gliclazide orchlorpropamide, other known sulfonylureas or other antihyperglycemicagents which act on the ATP-dependent channel of the □-cells, withglyburide and glipizide being preferred, which may be administered inthe same or in separate oral dosage forms.

[0276] The compounds of structure I will be employed in a weight ratioto the sulfonyl urea in the range from about 0.01: I to about 100: 1,preferably from about 0.02:1 to about 5:1.

[0277] The oral antidiabetic agent may also be a glucosidase inhibitorsuch as acarbose (disclosed in U.S. Pat. No. 4,904,769) or miglitol(disclosed in U.S. Pat. No. 4,639,436), which may be administered in thesame or in a separate oral dosage forms.

[0278] The compounds of structure I will be employed in a weight ratioto the glucosidase inhibitor within the range from about 0.01:1 to about100:1, preferably from about 0.05:1 to about 10:1.

[0279] The compounds of structure I may be employed in combination witha PPAR γ agonist such as a thiazolidinedione oral anti-diabetic agent orother insulin sensitizers (which has an insulin sensitivity effect inNIDDM patients) such as troglitazone (Wamer-Lambert's Rezulin®,disclosed in U.S. Pat. No. 4,572,912), rosiglitazone (SKB), pioglitazone(Takeda), Mitsubishi's MCC-555 (disclosed in U.S. Pat. No. 5,594,016),Glaxo-Welcome's GL-262570, englitazone (CP-68722, Pfizer) ordarglitazone (CP-86325, Pfizer, isaglitazone (MIT/J&J), JTT-501(JPNT/P&U), L-895645 (Merck), R-119702 (Sankyo/WL), NN-2344 (Dr.Reddy/NN), or YM-440 (Yamanouchi), preferably rosiglitazone andpioglitazone.

[0280] The compounds of structure I will be employed in a weight ratioto the thiazolidinedione in an amount within the range from about 0.01:1to about 100:1, preferably from about 0.05 to about 10:1.

[0281] The sulfonyl urea and thiazolidinedione in amounts of less thanabout 150 mg oral antidiabetic agent may be incorporated in a singletablet with the compounds of structure I.

[0282] The compounds of structure I may also be employed in combinationwith a antihyperglycemic agent such as insulin or with glucagon-likepeptide-1 (GLP-1) such as GLP-1(1-36) amide, GLP-1 (7-36) amide,GLP-1(7-37) (as disclosed in U.S. Pat. No. 5,614,492 to Habener, thedisclosure of which is incorporated herein by reference), as well asAC2993 (Amylin) and LY-315902 (Lilly), which may be administered viainjection, intranasal, inhalation or by transdermal or buccal devices.

[0283] Where present, metformin, the sulfonyl ureas, such as glyburide,glimepiride, glipyride, glipizide, chlorpropamide and gliclazide and theglucosidase inhibitors acarbose or miglitol or insulin (injectable,pulmonary, buccal, or oral) may be employed in formulations as describedabove and in amounts and dosing as indicated in the Physician's DeskReference (PDR).

[0284] Where present, metformin or salt thereof may be employed inamounts within the range from about 500 to about 2000 mg per day whichmay be administered in single or divided doses one to four times daily.

[0285] Where present, the thiazolidinedione anti-diabetic agent may beemployed in amounts within the range from about 0.01 to about 2000mg/day which may be administered in single or divided doses one to fourtimes per day.

[0286] Where present insulin may be employed in formulations, amountsand dosing as indicated by the Physician's Desk Reference.

[0287] Where present GLP-1 peptides may be administered in oral buccalformulations, by nasal administration or parenterally as described inU.S. Pat. Nos. 5,346,701 (TheraTech), 5,614,492 and 5,631,224 which areincorporated herein by reference.

[0288] The other antidiabetic agent may also be a PPAR α/γ dual agonistsuch as AR-H039242 (Astra/Zeneca), GW-409544 (Glaxo-Wellcome), KRP297(Kyorin Merck) as well as those disclosed by Murakami et al, “A NovelInsulin Sensitizer Acts As a Coligand for PeroxisomeProliferation-Activated Receptor Alpha (PPAR alpha) and PPAR gamma.Effect on PPAR alpha Activation on Abnormal Lipid Metabolism in Liver ofZucker Fatty Rats”, Diabetes 47, 1841-1847 (1998).

[0289] The antidiabetic agent may be an SGLT2 inhibitor such asdisclosed in U.S. application Ser. No. 09/679,027, filed Oct. 4, 2000(attorney file LA49 NP), employing dosages as set out therein. Preferredare the compounds designated as preferred in the above application.

[0290] The antidiabetic agent may be an aP2 inhibitor such as disclosedin U.S. application Ser. No. 09/391,053, filed Sep. 7, 1999, and in U.S.application Ser. No. 09/519,079, filed Mar. 6, 2000 (attorney file LA27NP), employing dosages as set out herein. Preferred are the compoundsdesignated as preferred in the above application.

[0291] The antidiabetic agent may be a DP4 inhibitor such as disclosedin U.S. application Ser. No. 09/788,173 filed Feb. 16, 2001 (attorneyfile LA50), WO99/38501, WO99/46272, WO99/67279 (PROBIODRUG), WO99/67278(PROBIODRUG), WO99/61431 (PROBIODRUG), NVP-DPP728A(1-[[[2-[(5-cyanopyridin-2-yl)amino]ethyl]amino]acetyl]-2-cyano-(S)-pyrrolidine)(Novartis) (preferred) as disclosed by Hughes et al, Biochemistry,38(36), 11597-11603, 1999, TSL-225(tryptophyl-1,2,3,4-tetrahydro-isoquinoline-3-carboxylic acid (disclosedby Yamada et al, Bioorg. & Med. Chem. Lett. 8 (1998) 1537-1540,2-cyanopyrrolidides and 4-cyanopyrrolidides as disclosed by Ashworth etal, Bioorg. & Med. Chem. Lett., Vol. 6, No. 22, pp 1163-1166 and2745-2748 (1996) employing dosages as set out in the above references.

[0292] The meglitinide which may optionally be employed in combinationwith the compound of formula I of the invention may be repaglinide,nateglinide (Novartis) or KAD1229 (PF/Kissei), with repaglinide beingpreferred.

[0293] The compound of formula I will be employed in a weight ratio tothe meglitinide, PPAR γ agonist, PPAR α/γ dual agonist, aP2 inhibitor,DP4 inhibitor or SGLT2 inhibitor within the range from about 0.01:1 toabout 100:1, preferably from about 0.05 to about 10:1.

[0294] The other type of therapeutic agent which may be optionallyemployed with a compound of formula I may be 1, 2, 3 or more of ananti-obesity agent including a beta 3 adrenergic agonist, a lipaseinhibitor, a serotonin (and dopamine) reuptake inhibitor, an aP2inhibitor, a thyroid receptor agonist and/or an anorectic agent.

[0295] The beta 3 adrenergic agonist which may be optionally employed incombination with a compound of formula I may be AJ9677(Takeda/Dainippon), L750355 (Merck), or CP331648 (Pfizer) or other knownbeta 3 agonists as disclosed in U.S. Pat. Nos. 5,541,204, 5,770,615,5,491,134, 5,776,983 and 5,488,064, with AJ9677, L750,355 and CP331648being preferred.

[0296] The lipase inhibitor which may be optionally employed incombination with a compound of formula I may be orlistat or ATL-962(Alizyme), with orlistat being preferred.

[0297] The serotonin (and dopoamine) reuptake inhibitor which may beoptionally employed in combination with a compound of formula I may besibutramine, topiramate (Johnson & Johnson) or axokine (Regeneron), withsibutramine and topiramate being preferred.

[0298] The thyroid receptor agonist which may be optionally employed incombination with a compound of formula I may be a thyroid receptorligand as disclosed in WO97/21993 (U. Cal SF), WO99/00353 (KaroBio),GB98/284425 (KaroBio), and U.S. Provisional Application No. 60/183,223filed Feb. 17, 2000, with compounds of the KaroBio applications and theabove U.S. provisional application being preferred.

[0299] The anorectic agent which may be optionally employed incombination with a compound of formula I may be dexamphetamine,phentermine, phenylpropanolamine or mazindol, with dexamphetamine beingpreferred.

[0300] The various anti-obesity agents described above may be employedin the same dosage form with the compound of formula I or in differentdosage forms, in dosages and regimens as generally known in the art orin the PDR.

[0301] The antihypertensive agents which may be employed in combinationwith the compound of formula I of the invention include ACE inhibitors,angiotensin II receptor antagonists, NEP/ACE inhibitors, as well ascalcium channel blockers, β-adrenergic blockers and other types ofantihypertensive agents including diuretics.

[0302] The angiotensin converting enzyme inhibitor which may be employedherein includes those containing a mercapto (—S—) moiety such assubstituted proline derivatives, such as any of those disclosed in U.S.Pat. No. 4,046,889 to Ondetti et al mentioned above, with captopril,that is, 1-[(2S)-3-mercapto-2-methylpropionyl]-L-proline, beingpreferred, and mercaptoacyl derivatives of substituted prolines such asany of those disclosed in U.S. Pat. No. 4,316,906 with zofenopril beingpreferred.

[0303] Other examples of mercapto containing ACE inhibitors that may beemployed herein include rentiapril (fentiapril, Santen) disclosed inClin. Exp. Pharmacol. Physiol. 10:131 (1983); as well as pivopril andYS980.

[0304] Other examples of angiotensin converting enzyme inhibitors whichmay be employed herein include any of those disclosed in U.S. Pat. No.4,374,829 mentioned above, withN-(1-ethoxycarbonyl-3-phenylpropyl)-L-alanyl-L-proline, that is,enalapril, being preferred, any of the phosphonate substituted amino orimino acids or salts disclosed in U.S. Pat. No. 4,452,790 with(S)-1-[6-amino-2-[[hydroxy-(4-phenylbutyl)phosphinyl]oxy]-1-oxohexyl]-L-prolineor (ceronapril) being preferred, phosphinylalkanoyl prolines disclosedin U.S. Pat. No. 4,168,267 mentioned above with fosinopril beingpreferred, any of the phosphinylalkanoyl substituted prolines disclosedin U.S. Pat. No. 4,337,201, and the phosphonamidates disclosed in U.S.Pat. No. 4,432,971 discussed above.

[0305] Other examples of ACE inhibitors that may be employed hereininclude Beecham's BRL 36,378 as disclosed in European Patent ApplicationNos. 80822 and 60668; Chugai's MC-838 disclosed in C.A. 102:72588v andJap. J. Pharmacol. 40:373 (1986); Ciba-Geigy's CGS 14824(3-([1-ethoxycarbonyl-3-phenyl-(1S)-propyl]amino)-2,3,4,5-tetrahydro-2-oxo-1-(3S)-benzazepine-1acetic acid HCl) disclosed in U.K. Patent No. 2103614 and CGS 16,617(3(S)-[[(1S)-5-amino-1-carboxypentyl]amino]-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepine-1-ethanoicacid) disclosed in U.S. Pat. No. 4,473,575; cetapril (alacepril,Dainippon) disclosed in Eur. Therap. Res. 39:671 (1986); 40:543 (1986);ramipril (Hoechsst) disclosed in Euro. Patent No. 79-022 and Curr. Ther.Res. 40:74 (1986); Ru 44570 (Hoechst) disclosed in Arzneimittelforschung34:1254 (1985), cilazapril (Hoffman-LaRoche) disclosed in J. Cardiovasc.Pharmacol. 9:39 (1987); R 31-2201 (Hoffman-LaRoche) disclosed in FEBSLett. 165:201 (1984); lisinopril (Merck), indalapril (delapril)disclosed in U.S. Pat. No. 4,385,051; indolapril (Schering) disclosed inJ. Cardiovasc. Pharmacol. 5:643, 655 (1983), spirapril (Schering)disclosed in Acta. Pharmacol. Toxicol. 59 (Supp. 5):173 (1986);perindopril (Servier) disclosed in Eur. J. Clin. Pharmacol. 31:519(1987); quinapril (Warner-Lambert) disclosed in U.S. Pat. No. 4,344,949and C1925 (Warner-Lambert)([3S-[2[R(*)R(*)]]3R(*)]-2-[2-[[1-(ethoxy-carbonyl)-3-phenylpropyl]amino]-1-oxopropyl]-1,2,3,4-tetrahydro-6,7-dimethoxy-3-isoquinolinecarboxylicacid HCl)disclosed in Pharmacologist 26:243, 266 (1984), WY-44221(Wyeth) disclosed in J. Med. Chem. 26:394 (1983).

[0306] Preferred ACE inhibitors are captopril, fosinopril, enalapril,lisinopril, quinapril, benazepril, fentiapril, ramipril and moexipril.

[0307] NEP/ACE inhibitors may also be employed herein in that theypossess neutral endopeptidase (NEP) inhibitory activity and angiotensinconverting enzyme (ACE) inhibitory activity. Examples of NEP/ACEinhibitors suitable for use herein include those disclosed in U.S. Pat.Nos. 5,362,727, 5,366,973, 5,225,401, 4,722,810, 5,223,516, 4,749,688,U.S. Pat. No. 5,552,397, U.S. Pat. No. 5,504,080, U.S. Pat. No.5,612,359,U.S. Pat. No. 5,525,723, European Patent Application 0599,444,0481,522, 0599,444, 0595,610, European Patent Application 0534363A2,534,396 and 534,492, and European Patent Application 0629627A2.

[0308] Preferred are those NEP/ACE inhibitors and dosages thereof whichare designated as preferred in the above patents/applications which U.S.patents are incorporated herein by reference; most preferred areomapatrilat, BMS 189,921([S—(R*,R*)]-hexahydro-6-[(2-mercapto-1-oxo-3-phenylpropyl)amino]-2,2-dimethyl-7-oxo-1H-azepine-1-aceticacid (gemopatrilat)) and CGS 30440.

[0309] The angiotensin II receptor antagonist (also referred to hereinas angiotensin II antagonist or AII antagonist) suitable for use hereinincludes, but is not limited to, irbesartan, losartan, valsartan,candesartan, telmisartan, tasosartan or eprosartan, with irbesartan,losartan or valsartan being preferred.

[0310] A preferred oral dosage form, such as tablets or capsules, willcontain the ACE inhibitor or AII antagonist in an amount within therange from abut 0.1 to about 500 mg, preferably from about 5 to about200 mg and more preferably from about 10 to about 150 mg.

[0311] For parenteral administration, the ACE inhibitor, angiotensin IIantagonist or NEP/ACE inhibitor will be employed in an amount within therange from about 0.005 mg/kg to about 10 mg/kg and preferably from about0.01 mg/kg to about 1 mg/kg.

[0312] Where a drug is to be administered intravenously, it will beformulated in conventional vehicles, such as distilled water, saline,Ringer's solution or other conventional carriers.

[0313] It will be appreciated that preferred dosages of ACE inhibitorand AII antagonist as well as other antihypertensives disclosed hereinwill be as set out in the latest edition of the Physician's DeskReference (PDR).

[0314] Other examples of preferred antihypertensive agents suitable foruse herein include omapatrilat (Vanlev®) amlodipine besylate (Norvasc®),prazosin HCl (Minipress®), verapamil, nifedipine, nadolol, diltiazem,felodipine, nisoldipine, isradipine, nicardipine, atenolol, carvedilol,sotalol, terazosin, doxazosin, propranolol, and clonidine HCl(Catapres®).

[0315] Diuretics which may be employed in combination with compounds offormula I include hydrochlorothiazide, torasemide, furosemide,spironolactono, and indapamide.

[0316] Antiplatelet agents which may be employed in combination withcompounds of formula I of the invention include aspirin, clopidogrel,ticlopidine, dipyridamole, abciximab, tirofiban, eptifibatide,anagrelide, and ifetroban, with clopidogrel and aspirin being preferred.

[0317] The antiplatelet drugs may be employed in amounts as indicated inthe PDR. Ifetroban may be employed in amounts as set out in U.S. Pat.No. 5,100,889.

[0318] Antiosteoporosis agents suitable for use herein in combinationwith the compounds of formula I of the invention include parathyroidhormone or bisphosphonates, such as MK-217 (alendronate) (Fosamax®).

[0319] Dosages employed for the above drugs will be as set out in thePhysician's Desk Reference.

Pharmaceutical Formulations

[0320] The pharmaceutical composition of the invention includes apharmaceutically acceptable carrier, adjuvant or vehicle that may beadministered to a subject, together with a compound of the presentinvention, and which does not destroy the pharmacological activitythereof. Pharmaceutically acceptable carriers, adjuvants and vehiclesthat may be used in the pharmaceutical compositions of the presentinvention include, but are not limited to, the following: ionexchangers, alumina, aluminum stearate, lecithin, self-emulsifying drugdelivery systems (“SEDDS”) such as d(-tocopherol polyethyleneglycol 1000succinate), surfactants used in pharmaceutical dosage forms such asTweens or other similar polymeric delivery matrices, serum proteins suchas human serum albumin, buffer substances such as phosphates, glycine,sorbic acid, potassium sorbate, partial glyceride mixtures of saturatedvegetable fatty acids, water, salts or electrolytes such as protaminesulfate, disodium hydrogen phosphate, potassium hydrogen phosphate,sodium chloride, zinc salts, colloidal silica, magnesium trisilicate,polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol,sodium carboxymethylcellulose, polyacrylates, waxes,polyethylene-polyoxypropylene-block polymers, polyethylene glycol andwool fat. Cyclodextrins such as α-, β- and γ-cyclodextrin, or chemicallymodified derivatives such as hydroxyalkylcyclodextrins, including 2- and3-hydroxypropyl-β-cyclodextrins, or other solubilized derivatives mayalso be used to enhance delivery of the modulators of the presentinvention.

[0321] The compositions of the present invention may contain othertherapeutic agents as described below, and may be formulated, forexample, by employing conventional solid or liquid vehicles or diluents,as well as pharmaceutical additives of a type appropriate to the mode ofdesired administration (for example, excipients, binders, preservatives,stabilizers, flavors, etc.) according to techniques such as those wellknown in the art of pharmaceutical formulation.

[0322] The compounds of the invention may be administered by anysuitable means, for example, orally, such as in the form of tablets,capsules, granules or powders; sublingually; buccally; parenterally,such as by subcutaneous, intravenous, intramuscular, or intrasternalinjection or infusion techniques (e.g., as sterile injectable aqueous ornon-aqueous solutions or suspensions); nasally such as by inhalationspray; topically, such as in the form of a cream or ointment; orrectally such as in the form of suppositories; in dosage unitformulations containing non-toxic, pharmaceutically acceptable vehiclesor diluents. The compounds of the invention may, for example, beadministered in a form suitable for immediate release or extendedrelease. Immediate release or extended release may be achieved by theuse of suitable pharmaceutical compositions including the compounds ofthe invention, or, particularly in the case of extended release, by theuse of devices such as subcutaneous implants or osmotic pumps. Thecompounds of the invention may also be administered liposomally.

[0323] Exemplary compositions for oral administration includesuspensions which may contain, for example, microcrystalline cellulosefor imparting bulk, alginic acid or sodium alginate as a suspendingagent, methylcellulose as a viscosity enhancer, and sweeteners orflavoring agents such as those known in the art; and immediate releasetablets which may contain, for example, microcrystalline cellulose,dicalcium phosphate, starch, magnesium stearate and/or lactose and/orother excipients, binders, extenders, disintegrants, diluents andlubricants such as those known in the art. The present compunds may alsobe delivered through the oral cavity by sublingual and/or buccaladministration. Molded tablets, compressed tablets or freeze-driedtablets are exemplary forms which may be used. Exemplary compositionsinclude those formulating the compound(s) of the invention with fastdissolving diluents such as mannitol, lactose, sucrose and/orcyclodextrins. Also included in such formulations may be high molecularweight excipients such as celluloses (Avicel) or polyethylene glycols(PEG). Such formulations may also include an excipient to aid mucosaladhesion such as hydroxy propyl cellulose (HPC), hydroxy propyl methylcellulose (HPMC), sodium carboxy methyl cellulose (SCMC), maleicanhydride copolymer (e.g., Gantrez), and agents to control release suchas polyacrylic copolymer (e.g., Carbopol 934). Lubricants, glidants,flavors, coloring agents and stabilizers may also be added for ease offabrication and use.

[0324] Exemplary compositions for nasal aerosol or inhalationadministration include solutions in saline which may contain, forexample, benzyl alcohol or other suitable preservatives, absorptionpromoters to enhance bioavailability, and/or other solubilizing ordispersing agents such as those known in the art.

[0325] Exemplary compositions for parenteral administration includeinjectable solutions or suspensions which may contain, for example,suitable non-toxic, parenterally acceptable diluents or solvents, suchas mannitol, 1,3-butanediol, water, Ringer's solution, an isotonicsodium chloride solution, or other suitable dispersing or wetting andsuspending agents, including synthetic mono- or diglycerides, and fattyacids, including oleic acid. The term “parenteral” as used hereinincludes subcutaneous, intracutaneous, intravenous, intramuscular,intraarticular, intraarterial, intrasynovial, intrasternal, intrathecal,intralesional and intracranial injection or infusion techniques.

[0326] Exemplary compositions for rectal administration includesuppositories which may contain, for example, a suitable non-irritatingexcipient, such as cocoa butter, synthetic glyceride esters orpolyethylene glycols, which are solid at ordinary temperatures, butliquify and/or dissolve in the rectal cavity to release the drug.

[0327] Exemplary compositions for topical administration include atopical carrier such as Plastibase (mineral oil gelled withpolyethylene).

[0328] The effective amount of a compound of the present invention maybe determined by one of ordinary skill in the art, and includesexemplary dosage amounts for an adult human of from about 0.1 to 500mg/kg of body weight of active compound per day, or between 5 and 2000mg per day which may be administered in a single dose or in the form ofindividual divided doses, such as from 1 to 5 times per day. It will beunderstood that the specific dose level and frequency of dosage for anyparticular subject may be varied and will depend upon a variety offactors including the activity of the specific compound employed, themetabolic stability and length of action of that compound, the species,age, body weight, general health, sex and diet of the subject, the modeand time of administration, rate of excretion, drug combination, andseverity of the particular condition. Preferred subjects for treatmentinclude animals, most preferably mammalian species such as humans, anddomestic animals such as dogs, cats and the like.

[0329] A typical capsule for oral administration contains compounds ofstructure I (250 mg), lactose (75 mg) and magnesium stearate (15 mg).The mixture is passed through a 60 mesh sieve and packed into a No. 1gelatin capsule.

[0330] A typical injectable preparation is produced by asepticallyplacing 250 mg of compounds of structure I into a vial, asepticallyfreeze-drying and sealing. For use, the contents of the vial are mixedwith 2 mL of physiological saline, to produce an injectable preparation.

[0331] The compounds of formula I of the invention are glucocorticoidreceptor modulators as shown by their ability to bind glucocorticoidreceptors in GR binding assays.

[0332] Compounds of formula I of the invention may also inhibit AP-1activity as indicated in cellular transrespressional assays, and causenone to minimal transactivation as indicated in cellulartransscriptional assays.

[0333] The GR binding assay, cellular transrespressional assay andcellular transcriptional assay employed are described in copendingprovisional application No. 60/396,907, filed Jul. 18, 2002 (attorneydocket D0250 PSP) which is incorporated herein by reference.

[0334] The following abbreviations are employed in the Examples:

[0335] Ph=phenyl

[0336] Bn=benzyl

[0337] t-Bu=tertiary butyl

[0338] Me=methyl

[0339] Et=ethyl

[0340] TMS=trimethylsilyl

[0341] TMSN₃=trimethylsilyl azide

[0342] TBS=tert-butyldimethylsilyl

[0343] FMOC=fluorenylmethoxycarbonyl

[0344] Boc=tert-butoxycarbonyl

[0345] Cbz=carbobenzyloxy or carbobenzoxy or benzyloxycarbonyl

[0346] THF=tetrahydrofuran

[0347] Et₂O=diethyl ether

[0348] hex=hexanes

[0349] EtOAc=ethyl acetate

[0350] DMF=dimethyl formamide

[0351] MeOH=methanol

[0352] EtOH=ethanol

[0353] i-PrOH=isopropanol

[0354] DMSO=dimethyl sulfoxide

[0355] DME=1,2 dimethoxyethane

[0356] DCE=1,2 dichloroethane

[0357] HMPA=hexamethyl phosphoric triamide

[0358] HOAc or AcOH=acetic acid

[0359] TFA=trifluoroacetic acid

[0360] TFAA=trifluoroacetic anhydride

[0361] i-Pr₂NEt=diisopropylethylamine

[0362] Et₃N=triethylamine

[0363] NMM=N-methyl morpholine

[0364] DMAP=4-dimethylaminopyridine

[0365] NaBH₄=sodium borohydride

[0366] NaBH(OAc)₃=sodium triacetoxyborohydride

[0367] DIBALH=diisobutyl aluminum hydride

[0368] LAH or LiAlH₄=lithium aluminum hydride

[0369] n-BuLi=n-butyllithium

[0370] LDA=lithium diisopropylamide

[0371] Pd/C=palladium on carbon

[0372] PtO₂=platinum oxide

[0373] KOH=potassium hydroxide

[0374] NaOH=sodium hydroxide

[0375] LiOH=lithium hydroxide

[0376] K₂CO₃=potassium carbonate

[0377] NaHCO₃=sodium bicarbonate

[0378] DBU=1,8-diazabicyclo[5.4.0]undec-7-ene

[0379] EDC (or EDC.HCl) or EDCI (or EDCI.HCl) orEDAC=3-ethyl-3′-(dimethylamino)propyl-carbodiimide hydrochloride (or1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride)

[0380] HOBT or HOBT.H₂O=1-hydroxybenzotriazole hydrate

[0381] HOAT=1-Hydroxy-7-azabenzotriazole

[0382] BOP reagent=benzotriazol-1-yloxy-tris (dimethylamino) phosphoniumhexafluorophosphate

[0383] NaN(TMS)₂=sodium hexamethyldisilazide or sodiumbis(trimethylsilyl)amide

[0384] Ph₃P=triphenylphosphine

[0385] Pd(OAc)₂=Palladium acetate

[0386] (Ph₃P)₄Pd^(o)=tetrakis triphenylphosphine palladium

[0387] DEAD=diethyl azodicarboxylate

[0388] DIAD=diisopropyl azodicarboxylate

[0389] Cbz-Cl=benzyl chloroformate

[0390] CAN=ceric ammonium nitrate

[0391] SAX=Strong Anion Exchanger

[0392] SCX=Strong Cation Exchanger

[0393] Ar=argon

[0394] N₂=nitrogen

[0395] min=minute(s)

[0396] h or hr=hour(s)

[0397] L=liter

[0398] μL=milliliter

[0399] Li=microliter

[0400] g=gram(s)

[0401] mg=milligram(s)

[0402] mol=moles

[0403] mmol=millimole(s)

[0404] meq=milliequivalent

[0405] RT=room temperature

[0406] sat or sat'd=saturated

[0407] aq.=aqueous

[0408] TLC=thin layer chromatography

[0409] HPLC=high performance liquid chromatography

[0410] LC/MS=high performance liquid chromatography/mass spectrometry

[0411] MS or Mass Spec=mass spectrometry

[0412] NMR=nuclear magnetic resonance

[0413] NMR spectral data: s=singlet; d=doublet; m=multiplet; br=broad;t=triplet mp=melting point

Preparations

[0414] The preparations set out below are for the synthesis of reagentsthat were not obtained from commercial sources and were employed for thepreparation of compounds of formula I of the invention. All chemicalstructures in the tables and schemes are racemic unless specifiedotherwise.

Preparation I 2-Amino-4-[1-(4-fluoro)naphthyl]thiazole 1a

[0415]

[0416] Step 1

[0417] To a solution of 4‘-fluoro-l’-acetonaphthone (28.69 mmol, 5.4 g)in 1,4-dioxane (18.0 mL) at 0° C. was added bromine (35.13 mmol, 5.61g). After 3 hours at room temperature the reaction mixture wasconcentrated in vacuo to give 7.66 g (Y: 100%) of the product of step 1.

[0418] Step 2

[0419] To a solution of the product of step 1 (28.69 mmol, 7.66 g) inethyl alcohol (20 mL) at room temperature was added thiourea (36.13mmol, 2.75 g). After 1 hour at room temperature a precipitate formed. Tothe reaction mixture was added water (100 mL) and the solid wascollected by vacuum filtration. The solid was then washed with water(3×100 mL) and dichloromethane (3×100 mL). The solid was then dried invacuo to give 5.5 g (Y: 75%) of the title compound 1a. MS (E+) m/z: 245(MH⁺).

[0420] In a similar manner the following compounds were prepared fromthe corresponding ketone. Preparation Structure 1b

1c

1d

1e

1f

1g

1h

1i

1j

1k

1l

1m

1n

1o

1p

1q

1r

1s

1t

1u

1v

1w

Preparation 2 2-Amino-4-[1-(4-fluoro)naphthyl]imidazole 2a

[0421]

[0422] Step 1

[0423] To a solution of the product of preparation 1a, step 1 (18.73mmol, 5.0 g) in DMF (15 mL) at room temperature was added1-acetylguanidine (57.43 mmol, 5.80 g). After 5 hours at roomtemperature, the reaction mixture was diluted with water (100 mL) andextracted with ethyl acetate (3×100 mL). The organic phases wereconcentrated in vacuo and the residue chromatographed on silica gel(eluted with 5% methanol in dichloromethane) to give 2.0 g (Y: 39%) ofthe product of step 1. MS (E+) m/z: 270 (MH⁺).

[0424] Step 2

[0425] To a solution of the product of step 1 (7.43 mmol, 2.0 g) inmethanol (17 mL) was added water (8.5 mL) and 12 N HCl (12.0 mL). After1 hour at reflux the reaction mixture was concentrated in vacuo toapproximately 15 mL. The resulting solution was then purified andneutralized by cation exchange SPE to give 1.66 g (Y: 99%) of the titlecompound 2a. MS (E+) m/z: 228 (MH⁺).

[0426] In a similar manner the following compounds were prepared fromthe corresponding ketones. Preparation Structure 2b

2c

2d

2e

Preparation 3 2-Amino-4-(1-naphthyl)oxazole 3a

[0427]

[0428] Step I

[0429] To a solution of 1-acetonaphthone (29.38 mmol, 5.0 g) in glacialacetic acid (10.0 mL) at RT was added bromine (30.06 mmol, 4.80 g) inglacial acetic acid (5.0 mL). After 5 minutes the reaction mixture waspoured onto crushed ice and extracted with dichloromethane to give 7.31g (Y: 100%) of the product of step 1. MS (E+) m/z: 250 (MH⁺).

[0430] Step 2

[0431] To a solution of the product of step 1 (5.50 mmol, 1.37 g) inethyl alcohol (10 mL) was added urea (27.50 mmol, 1.65 g). After 2 hoursat reflux the reaction mixture was concentrated in vacuo and the residuechromatographed on silica gel (eluted with 30% ethyl acetate in hexane)to give 100 mg (Y: 9%) of the title compound 3a. MS (E+) m/z: 211 (MH⁺).

Preparation 4 5-(1-Naphthyl)-3-aminoisoxazole 4a

[0432]

[0433] Step 1

[0434] To a solution of acetonitrile (12.18 mmol, 0.50 g) in THF (10.0mL) was added 60% sodium hydride (24.36 mmol, 0.975 g), followed by1-naphthoic acid methyl ester (12.18 mmol, 2.27 g). After 2 hours at 70°C. the reaction mixture was quenched with an excess of 1N HCl andextracted with dichloromethane (3×30 mL). The organic phases wereconcentrated in vacuo and the residue was chromatographed on silica gel(eluted with 33% ethyl acetate in hexane) to give 1.80 g (Y: 76%) of theproduct of step 1. MS (E+) m/z: 196 (MH⁺).

[0435] Step 2

[0436] Hydroxylamine sulfate (1.61 mmol, 264 mg) was added to a stirredsolution of the product of step 1 (2.94 mmol, 573 mg) and NaOH (3.53mmol, 141 mg) in 50% aq. EtOH (6.0 mL). The mixture was heated at 80° C.for 5 hours and then stirred at RT for 14 hours. The reaction mixturewas quenched with an excess of 1N HCl, washed with dichloromethane (3×50mL), neutralized with saturated sodium bicarbonate solution andextracted with dichloromethane (3×50 mL). The organic extracts werecombined, dried over Na₂SO₄ and concentrated under vacuo to give 237 mg(Y: 38%) of the title compound 4a. MS (E+) m/z: 211 (MH⁺).

Preparation 5 3-(1-Naphthyl)-5-aminopyrazole 5a

[0437]

[0438] To a solution of the product of preparation 4, step 1 (2.70 mmol,527 mg) in EtOH (5.0 mL) was added hydrazine (2.70 mmol, 85 mg). Theresulting mixture was refluxed for 2 h, cooled, diluted with 1N HCl,washed with dichloromethane (3×50 mL), neutralized with saturated sodiumbicarbonate solution and extracted with dichloromethane (3×50 mL). Theorganic extracts were combined, dried over Na₂SO₄ and concentrated undervacuum to give 280 mg (Y: 51%) of the title compound Sa. MS (E+) m/z:210 (MH⁺).

Preparation 6 4-[1-(6-Methoxy)naphthyl]-2-aminothiazole 6a

[0439]

[0440] Step 1

[0441] To a solution of 6-methoxy-1-naphthoic acid (0.5 g, 2.47 mmol,1.0 equi.) in dichloromethane (10 mL) at room temperature was added asolution of oxalyl chloride (2M in dichloromethane, 2.5 mL, 5.0 mmol, 2equi.). The solution was stirred at room temperature for 2 hours, andthe excess oxalyl chloride removed in vacuo. The residue was dissolvedin methanol and stirred at room temperature for 18 hours. The solventwas removed in vacuo, yielding 0.45 g (84%) of the product of step 1:LC/MS (m/z 217, (M−H)⁺); ¹H NMR (CDCl₃) δ 8.82 (d, 1H), 8.03 (dd, 1H),7.90 (d, 1H), 7.44 (t, 1H), 7.26 (dd, 1H), 7.16 (s, 1H), 4.02 (s, 3H),3.95 (s, 3H).

[0442] Step 2

[0443] Reference: P. Chen, P. T. Cheng, S. H. Spergel, R. Zahler, X.Wang, J. Thottathil, J. C. Barrish, R. P. Polniaszek, TetrahedronLetters, 38, 3175 (1997).

[0444] To a solution of the product of step 1 (0.238 g, 1.1 mmol, 1.0equi.) and chloroiodomethane (0.32 mL, 4.4 mmol, 4 equi.) in THF (5 mL)was added a solution of LDA (2M, 2.2 mL, 4.0 equi.) in THF (10 mL)dropwise in 30 minutes, while keeping the solution temperature at −78°C. The reaction solution was stirred at −78° C. for 10 minutes. Asolution of acetic acid (1.5 mL) in THF (10 mL) was added in dropwise in10 minutes. After stirring for an additional 10 minutes at −78° C., thesolution was quenched with ethyl acetate and saturated sodium chloridesolution. The organic phase was washed with saturated sodium bisulfite,saturated sodium chloride, dried with sodium sulfate and concentrated invacuo. The residue was purified by flash chromatography (10% ethylacetate in hexane) to yield 0.23 g (90%) of the product of step 2: LC/MS(m/z 235, (M+H)⁺); ¹H NMR (CDCl₃) δ 8.82 (d, 1H), 8.03 (dd, 1H), 7.90(d, 1H), 7.44 (t, 1H), 7.26 (dd, 1H), 7.16 (s, 1H), 4.80 (s, 2H), 3.95(s, 3H).

[0445] Step 3

[0446] To a solution of the product of step 2 (0.23 g, 1.0 mmol, 1.0equi.) in ethanol (SmL) at room temperature was added thiourea (90 mg,1.2 mmol, 1.2 equi.). The reaction solution was stirred at roomtemperature for 2 hours, after which a yellow precipitate was formed.The reaction was quenched by addition of water and ethyl acetate. Theaqueous phase was extracted with ethyl acetate (3×). The combinedorganic phases were dried with sodium sulfate and concentrated in vacuoto yield 200 mg (78%) of the title compound 6a: LC/MS (m/z 235, (M+H)⁺);¹H NMR (CDCl₃) δ 8.1 (d, 1H), 7.9 (m, 1H), 7.43 (m, 2H), 7.25 (m, 1H),7.10 (dd, 1H), 6.65 (s, 1H), 3.95 (s, 3H).

[0447] In a similar manner the following compounds were prepared.Preparation Structure 6b

6c

Preparation 7 4-f 1-(6-Methoxy)naphthyl]-2-aminoimidazole 7a

[0448]

[0449] Step 1

[0450] To a solution of the product of preparation 6, step 2 (0.5 g,2.14 mmol, 1.0 equi.), in ethanol (5 mL) at room temperature was added1-acetylguanidine (650 mg, 6.42 mmol, 3.0 equi.). The reaction solutionwas stirred at room temperature for 24 hours. The reaction was quenchedby addition of water and ethyl acetate. The aqueous phase was extractedwith ethyl acetate (3×). The combined organic phases were dried withsodium sulfate and concentrated in vacuo to yield 0.2 g (35%) of theproduct of step 1: LC/MS (m/z 282, (M+H)⁺).

[0451] Step 2

[0452] To a solution of the product of step 1 (0.2 g, 0.7 mmol, 1.0equi.) in methanol (5 mL) was added water (1.0 mL) and hydrochloric acid(12N, 1.0 mL). The reaction solution was heated to reflux for 1 hour,after which the solvent was removed in vacuo. The crude mixture waspurified by cation exchange SPE to give 0.12 g (70%) of the titlecompound 7a: LC/MS (m/z 240, (M+H)⁺).

Preparation 8 4-(3-Pyridyl)-2-aminothiazole 8a

[0453]

[0454] Step 1

[0455] To a solution of 3-acetylpyridine (20.0 mmol, 2.42 g) in 48% HBr(10.0 mL) was added bromine (20.0 mmol, 3.2 g) in 48% HBr (4.0 mL). Thereaction mixture was heated to 65° C. for one hour and stirred at RT foran additional hour. The reaction mixture was quenched with ice andfiltered. The solid was washed with acetone (2×10 mL) and diethyl ether(2×10 mL). The solid was then dried in vacuo to give 3.70 g (Y: 83%) ofthe product of step 1.

[0456] Step 2

[0457] To a solution of the product of step 1 (6.10 mmol, 1.22 g) inethyl alcohol (10 mL) at room temperature was added thiourea (7.32 mmol,560 mg). After 1 hour at room temperature the reaction mixture wasquenched with water (30 mL) and washed with dichloromethane (3×100 mL).The aqueous layer was then purified by cation exchange chromatography togive 600 mg (Y: 56%) of the title compound 8a. MS (E+) m/z: 178 (MH⁺).

[0458] In a similar manner the following compounds were prepared.Preparation Structure 8b

8c

8d

Preparation 9 4-(1-Isoquinolinyl)-2-aminothiazole 9a

[0459]

[0460] Step 1

[0461] To a solution of 1-isoquinolinecarboxylic acid (11.55 mmol, 2.0g) in THF (20.0 mL) and methanol (10.0 mL) is addedtrimethylsilyldiazomethane (69.3 mmol, 32.0 mL of a 2 M solution inhexanes). After 2 h at RT the reaction mixture was concentrated in vacuoto give 1.17 g (Y: 99%) of the product of step 1. MS (E+) m/z: 188(MH⁺).

[0462] Step 2

[0463] To a solution of the product of step 1 (10.69 mmol, 2.0 g) indichloromethane (100.0 mL) was added trimethylaluminum (32.88 mmol,16.44 mL of a 2.0 M solution in toluene) at −78° C. After the additionwas complete the reaction was allowed to warm to 0° C. The reactionmixture was then quenched with water (30 mL) and extracted withdichloromethane (3×30 mL). The organic phases were concentrated in vacuoand the residue chromatographed on silica gel (eluted with 10% ethylacetate in hexanes) to give 930 mg (Y: 51%) of the product of step 2. MS(E+) m/z: 172 (MH⁺).

[0464] Step 3

[0465] The product of step 2 was converted to the title compound 9a asdescribed in preparation 8, step 2. MS (E+) m/z: 228 (MH⁺).

Preparation 10 5-(1-naphthyl)-2-aminopyridine 10a

[0466]

[0467] Potassium carbonate (5.19 mmol, 717 mg) in water (2.5 mL) andtetrakis(triphenylphosphine)palladium(0) (0.04 mol %, 80 mg) in ethylalcohol (2.5 mL) were added to 2-amino-5-bromopyridine (1.73 mmol, 299mg) and 1-naphthaleneboronic acid (2.60 mmol, 446 mg) in benzene (10.0mL). After 2 hours at 90° C. the reaction mixture was quenched withwater (30 mL) and extracted with dichloromethane (3×30 mL). The organicphases were concentrated in vacuo and the residue chromatographed onsilica gel (eluted with 50% ethyl acetate in hexanes) to give 260 mg (Y:68%) of the title compound 10a. MS (E+) m/z: 381 (MH⁺).

[0468] In a similar manner the following compounds were prepared.Preparation Structure 10b

10c

Preparation 11a 4-(2,3-Dihydro-benzo[1,4]dioxin-5-yl)-thiazol-2-ylamine

[0469]

[0470] Step 1

[0471] A suspension of 2,3-dihydroxy-benzoic acid methyl ester (336 mg,2 mmol) and cesium carbonate (1.56 g, 4.8 mmol) in DMF was stirred atroom temperature for 0.5 h. 1,2-Dibromoethane (0.224 ml, 2.6 mmol) wasadded to the DMF solution. The mixture was stirred at 80 C for 4 h, andthen diluted with ethyl acetate. The organic layer was washed with waterand brine, dried over anhydrous MgSO4, filtered and concentrated invacuo to give the crude product. It was chromatographed on silica gelwith EtOAc/hexane (20%-40%) as eluent to afford2,3-dihydro-benzo[1,4]dioxine-5-carboxylic acid methyl ester as a whitesolid. (223 mg, 1.14 mmol, 57.4% yield).

[0472] Step 2

[0473] Reference: Tetrahedron Lett, 1997, 3173-78

[0474] To a mixture of 2,3-dihydro-benzo[1,4]dioxine-5-carboxylic acidmethyl ester (100 mg, 0.515 mmol) and chloroiodomethane (0.075 ml, 1.03mmol) in 1 ml of THF was added a solution of LDA in THF (2M, 0.57 ml,1.13 mmol) dropwise at −78 C over 15 min. The reaction mixture wasstirred at −78 C for 10 min. A solution of acetic acid (0.75 ml) in THF(5 ml) was added dropwise over 5 min at −78 C. The resulting solutionwas stirred at the same temperature for additional 10 min. and was thenpartitioned between ethyl acetate and water. The organic layer waswashed with aqueous sodium bicarbonate, brine, dried over MgSO4 andconcentrated in vacuo to give the crude2-chloro-1-(2,3-dihydro-benzo[1,4]dioxin-5-yl)-ethanone as a light brownliquid.

[0475] Step 3

[0476] The crude product of step 2 was dissolved in EtOH (1.5 ml).Thiourea (76 mg, 1 mmol) was added followed by addition of TEA (0.14 ml,1 mmol). The solution was heated at 80 C for 6 h. After removal ofethanol, the reaction mixture was taken into ethyl acetate and aqueoussodium bicarbonate. The organic layer was washed with 0.5 N HCl. Afterseparation, the aqueous layer was adjusted to pH 9 with sodiumcarbonate, and extracted with ethyl acetate. The ethyl acetate solutionwas washed with brine, dried over MgSO4 and concentrated to give4-(2,3-dihydro-benzo[1,4]dioxin-5-yl)-thiazol-2-ylamine 11a as a brownsolid, 37 mg (0.16 mmol, 31% yield). ¹H NMR (CDCl₃) δ 7.46 (dd, 1H),7.04 (s, 1H), 6.75-6.83 (m, 2H), 5.33 (br s, 2H), 4.23-4.34 (m, 4H);LC/MS m/z 235 (M+H)⁺.

Preparation 11b 4-Benzo[1,3]dioxol-4-yl-thiazol-2-ylamine

[0477] Preparation 11b was prepared in a similar manner to preparation11a. Compound Structure 11b

Preparation 12a

[0478]

[0479] Step 1

[0480] To 1,3-dimethyl-4,6-dinitrobenzene (5.0 g, 25.489 mmol) undernitrogen in 50.0 mL DMF was added 10.16 mL N,N-dimethylformamidedimethyl acetal (76.468 mmol, 9.112 g, 3.0 eq). The mixture was stirredunder nitrogen at 140° C. for 5 h, allowed to cool to room temperatureand the solvent was removed under vacuum to afford a dark, black solid.To this solid was added 330 mL of 50% aqueous THF, followed by sodiumperiodate (32.7 g, 152.9 mmol, 6 eq). The solution turned red andproduced a slight exotherm. The mixture was allowed to stir at roomtemperature for 5 h. This mixture was then filtered through a scinteredglass funnel to remove excess solid material and rinsed with ethylacetate until colorless. (Total volume of eluent was 750 mL afterrinsing). The filtrate was washed with 100 mL saturated NaHCO_(3(aq)).The aqueous was extracted again with 200 mL ethyl acetate. The organiclayers were combined and dried over sodium sulfate. The solution wasconcentrated under vacuum. The remaining crude oil was chromatographedusing silica gel eluted with 30% ethyl acetate in hexanes to yield 2.77g of the product of step I as a yellow solid (48%).

[0481] Step 2

[0482] The product of step 1 (1.93 g, 8.62 mmol) and powdered iron (3.85g, 68.93 mmol, 8 eq) were placed into a flask containing 100 mL of a2:2:1 mixture of ethanol/acetic acid/water, respectively. The flask wasplaced into a 0° C. ice bath and allowed to equilibrate for 20 minutes.8 drops of concentrated HCl were added. The reaction began to changecolor (yellow to green to red/brown). After 1 hour, the cooling bath wasremoved and allowed to warm to room temperature. After stirring for anadditional 1 hour at room temperature, the mixture was filtered througha thin pad of celite. The filtrate was concentrated under vacuum toafford a yellow/green solid. This crude material was chromatographedusing silica gel eluted with 30% hexanes in ethyl acetate. Removal ofthe solvent under vacuum yielded 1.165 g of the product of step 2 as ayellow/orange solid (82%).

[0483] Step 3

[0484] To the product of step 2 (901 mg, 5.49 mmol) under nitrogen in30.0 mL ethanol was added 0.92 mL pyruvic acid (1.160 g, 13.173 mmol)followed by 13.0 mL of 2N aqueous sodium hydroxide. The mixture wasstirred at 80° C. for 5 hours. 0.6 N Aqueous ammonia (˜100 mL) was addedand the mixture was gently heated to 74° C. A 0.6N HCl/0.3N AcOHsolution was added until pH was ˜4 to precipitate the product. Themixture was filtered to collect solid which was dried under vacuum toobtain 1.303 g of the product of step 3 as a yellow solid (88%).

[0485] Step 4

[0486] The product of step 3 (99 mg, 0.369 mmol) and ˜3 mg Cu₂O (˜0.018mmol, 0.05 eq) were placed under nitrogen in 3.0 mL di(ethylene glycol)methyl ether. The mixture was stirred at 165° C. for 6 h and ˜30 mLconcentrated aqueous ammonia was added. The mixture was extracted with2×100 mL methylene chloride and dried over sodium sulfate, concentratedunder vacuum and chromatographed using silica gel eluted with 1%triethylamine, 7% methanol in chloroform. The eluent was removed undervacuum to obtain 44 mg of the product of step 4 as a brown crystallinesolid (67%) M+H=181.28.

[0487] Step 5

[0488] The product of step 4 (21 mg, 0.117 mmol), 49 μL methyl acrylicacid (50 mg, 0.583 mmol, 5 eq), and ˜3 mg hydroquinone were placed in atube under nitrogen in 1.0 mL xylenes. The tube was sealed with a teflonlined cap and heated at 140° C. for 3 days. LC/MS shows reaction iscomplete. The solvent was removed under vacuum and the crude materialwas chromatographed using silica gel eluted with 1% triethylamine, 10%methanol in chloroform to afford 21 mg of the title compound 12a as aclear oil (68%). M+H=267.14

Preparation 13

[0489]

[0490] Step 1

[0491] The product of preparation 12a, step 4 (128 mg, 0.710 mmol),ethyl methacrylate (442 μL, 3.551 mmol, 5 eq), and ˜20 mg hydroquinoneinto 5.0 mL xylenes were placed in a tube under nitrogen. The tube wassealed with a teflon lined cap and stirred at 140° C. for 3 days.Solvent was removed under vacuum and the crude material was directlypurified on prep HPLC. The retention times on the HPLC (both analyticaland prep) for the two isomeric products are very similar. 24 mgs of thepure minor isomer and 28 mg of a mixture of both the major and minorisomers was isolated.

[0492] Step 2

[0493] The minor product of step 1 (24 mg, 0.082 mmol) was placed undernitrogen in 1.5 mL methanol. 0.3 mL of 1N NaOH were added and themixture stirred at 60° C. for 2 hours. An additional 0.1 mL of saturatedaqueous NaOH were added and the mixture stirred an additional 5 h at 60°C. The mixture was allowed to cool, then 50 μL TFA were added. Themixture was purified directly on prep HPLC. Solvent was removed undervacuum to afford 21 mg of the title compound 13 as a clear oil (˜95%).M+H=267

Preparation 14

[0494]

[0495] Step I

[0496] Reference: B. Bacle and G. Levesque, Polymer Communications, 28,36 (1987).

[0497] A IL flask was charged with anthracene (14 g, 0.078 mol, 1.0equi.), hydroquinone (0.8 g, 0.008 mol, 0.1 equi.), methacrylic acid (14mL, 0.156 mol, 2.0 equi.) and xylene (500 mL). The solution was heatedto reflux for 1 day. The solution was cooled and concentrated in vacuo.The residue was dissolved in ethyl acetate and extracted with 1N NaOH(3×). The aqueous phase was acidified with 1N HCl, and the product wasextracted with ethyl acetate (3×). The combined organic phases wereconcentrated in vacuo to give the crude product mixture.Recrystallization with hexane and ethyl acetate to yield 8 g (40%) ofthe product of step 1, 14:LC/MS (m/z 263 (M−H)⁺); ¹H NMR (CDCl₃) δ7.08-7.25 (m, 8H), 4.37 (s, 1H), 4.25(t, 1H), 2.61 (dd, 1H), 1.39 (dd,1H), 1.07 (s, 3H).

[0498] Step 2

[0499] The product of step 1, 14 was resolved into its correspondingenantiomers, 14(R) and 14(S) by chiral preparative HPLC with thefollowing conditions, Column: Chiracel®-OJ, 5×50 cm, Mobile phase:trifluroacetic acid/acetonitrile: 1/1000 (vol/vol), Temperature:ambient, Flowrate: 70 mL/min, Injection: 1.5 grams in 50 mL solvent,Detection: UV (250 nm). Retention times for R-enantiomer, 30 min,S-enantiomer, 52 min. Analytical HPLC conditions, Column: Chiracel®-OJ,4.6×250 cm, Mobile phase: trifluroacetic acid/acetonitrile: 1/1000(vol/vol), Temperature: ambient, Flowrate: 1.5 mL/min, Detection: UV(250 nm). Retention times: R-enantiomer, 6.5 min, S-enantiomer, 15 min.

Preparation 15

[0500]

[0501] Acrylic acid and anthracene were reacted as described inpreparation 14 to provide compound 15.

[0502] Preparation 16a

[0503] To a solution of the product of step 1 preparation 14 (5.0 g,18.9 mmol, 1.0 equi.) in dichloromethane (20 mL) was added an oxalylchloride solution in dichloromethane (2M, 11.4 mL, 22.8 mmol, 1.2 equi.)dropwise. The solution was stirred at RT for 2 hours, after which thesolvent was removed in vacuo. The residue was dissolved in acetonitrile(20 mL) and added dropwise to a solution of ethylene glycol (1.27 mL,22.8 mmol, 1.2 equi.) in acetonitrile (20 mL). The reaction solution wasstirred at RT for 4 hours and then the solution was concentrated invacuo. Purification by flash chromatography (10% ethyl acetate inhexane) yielded 2.0 g (34%) of compound 16a: ¹H NMR (CDCl₃) δ 7.52 (d,1H), 7.09-7.27 (m, 8H), 4.40 (s, 1H), 4.31 (t, 1H), 4.11 (m, 1H), 4.0(m, 1H), 3.63 (m, 2H), 2.72 (dd, 1H), 1.42 (dd, 1H), 1.16 (s, 3H).

[0504] In a similar manner the following compounds were prepared fromthe corresponding acids and alcohols. Preparation Chiral NumberCompounds Structure 16b

16c

16d

16e Chiral (S)

16f Chiral (R)

16g Chiral (S)

16h Chiral (R)

Preparation 17

[0505]

[0506] Reference: P. V. Alston, R. M. Ottenbrite, J. Newby, J. Org.Chem., 44, 4939 (1979).

[0507] 9-Anthracenecarboxylic acid (4 g, 0.017 mol, 1.0 equi.) was addedto a mixture of methacrylic acid (20 mL, 0.23 mol, 14.0 equi.), benzene(20 mL) and hydroquinone (0.2 g, 0.0017 mol, 0.1 equi.). The solutionwas heated to reflux for 7 days. The solution was cooled and theprecipitate formed was filtered and washed with benzene. The precipitatewas recrystallized with hexane and ethyl acetate to yield 0.4 g (7.2%)of the ortho product 17a: MS (m/z 321(M−H)⁺); ¹H NMR (CDCl₃) δ 7.1-7.28(m, 8H), 4.25 (t, 1H), 4.06 (s, 3H), 2.25 (dd, 1H), 1.69 (dd, 1H), 1.08(s, 3H). The filtrate was extracted with 1N NaOH (3×). The aqueous phasewas acidified with 1N HCl, and the product was extracted with ethylacetate (3×). The organic phases were concentrated in vacuo.Recrystallization of the residue with hexane and ethyl acetate yielded0.2 g (4%) of the meta product 17b MS (m/z 321 (M−H)⁺); ¹H NMR (CDCl₃) δ7.16-7.27 (m, 8H), 4.36 (s, 1H), 4.08 (s, 3H), 2.90 (d, 1H), 1.67 (d,1H), 1.06 (s, 3H).

[0508] In a similar manner the following compounds were prepared frommethacrylic acid and the appropriate anthracene. Preparation NumberStructure 17C

17D

17E

17F

17G

17H

17I

17J

EXAMPLES

[0509] The following Examples represent preferred embodiments of theinvention.

Example 1

[0510]

[0511] Preparation 14 Heat, 18 hours Example 1 To a solution of theproduct of Preparation 14, step 1 (20 mg, 0.075 mmol, 1.0 equi.) inacetonitrile (2 mL) was added 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (DEC) (17 mg, 0.09 mmol, 1.2equi.), 1-hydroxy-7-azabenzotriazole (HOAt) (12 mg. 0.09 mmol, 1.2equi.), triethyl amine (0.025 mL, 0.18 mmol, 2.5 equi.), and2-amino-4,5-dimethylthiazole hydrochloride salt (14.8 mg, 0.09 mmol, 1.2equi.). The reaction solution was heated to 80° C. for 18 hours. Thereaction was then concentrated in vacuo. The product mixture waspurified by flash chromatography (20% ethyl acetate in hexane) to yield19.8 mg (70%) of Example 1. LC/MS (m/z 375, (M+H)+).

Examples 2 to 339

[0512] In a similar manner Examples 2-339 were prepared from thecoupling of the appropriate acids and amines. Preparations of amines oracids not commercially available are described in the precedingpreparations section of this document. All examples in the tables areracemic unless specified otherwise. Examples in the table where oneenantiomer predominates or is the sole component, are designated aseither R or S. Chiral MS: (M + H = Example Compounds Structure MW +1)  2

513.6  3

409.5  4

414.5  5

475.5  6

364.5  7

482.6  8

443.6  9

382.5  10

524.6  11

422.5  12

410.5  13

395.5  14

446.6  15

426.5  16

393.5  17

499.6  18

482.6  19

400.4  20

379.5  21

461.5  22

350.4  23

429.5  24

367.5  25

368.4  26

408.5  27

396.5  28

381.5  29

403.5  30

412.5  31

418.4  32

409.5  33

484.4  34

395.46  35

359.5  36

396.5  37

426.5  38

354.5  39

374.9 40-41

354.5  42

354.5  43

475.6  44

393.5  45

372.4  46

390.5  47

393.5  48

395.5  49

380.9  50

415.5  51

425.5  52

402.5  53

374.4  54

400.5  55

368.5  56

393.5  57

357.5  58

 59

369.5  60

369.5  61

383.5  62

399.5  63

399.5  64

422.4  65

422.4  66

413.5  67

409.5  68

329.4  69

360.5  70

432.5  71

397.5  72

370.5  73

446.6  74

368.5  75

383.5  76

354.5 77-78

354.5  79

390.5  80

357.5  81

390.5  82

446.6  83

373.5  84

383.5  85

343.4  86

360.5  87

437.6  88

390.5  89

374.4  90

369.5  91

422.4  92

383.5  93

383.5  94

427.5  95

399.5  96

399.5  97

396.5  98

413.5  99

413.5 100

399.5 101

379.47 102

329.41 103

461.5 104

422.6 105

457 106

402.6 107

481.5 108

458.5 109

432.5 110

436.6 111

485 112

472.6 113

481.6 114

410.5 115

424.6 116

431 117

426.5 118

410.5 119

341.4 120

414.5 121

396.5 122

450.6 123-124

341.4 125

385.4 126

354.5 127

431 128

486.52 129

441.51 130

402.56 131 Chiral (R)

472.61 132 Chiral (S)

472.61 133

344.4 134

345.4 135

354.5 136

357.5 137

358.4 138

381.4 139

385.4 140

386.5 141

395.5 142

401.5 143

403.5 144

403.5 145

405.5 146

405.5 147

409.5 148

469.6 149

472.6 150

497.5 151

422.55 152

458.59 153

472.61 154

466.59 155

490.6 156

456.55 157

478.64 158

386.5 159

389.5 160

389.5 161

417.6 162

403.5 163

417.6 164

432.57 165

417.6 166

417.6 167

391.5 168

423.5 169

431.6 170

390.5 171

397.5 172

486.64 173

455.56 174

466.59 175

452.58 176

502.64 177

462.57 178

502.64 179

440.5 180

440.5 181

467.6 182

436.6 183

455.6 184

440.5 185

457 186

457 187

467.6 188 Chiral (R)

486.64 189 Chiral (S)

486.64 190

467.58 191

526.7 192

498.7 193

510.7 194

490.6 195

541.7 196

436.6 197

466.6 198

541.7 199

454.6 200

476.6 201

534.7 202

459.6 203

462.6 204

469.59 205

405.5 206

502.64 207 Chiral (R)

490.6 208 Chiral (S)

490.6 209

464.63 210

385.51 211

493.68 212

551.51 213 Chiral (S)

502.64 214 Chiral (R)

502.64 215

473.55 216 Chiral (S)

455.56 217 Chiral (R)

455.56 218 Chiral (S)

469.59 219 Chiral (R)

469.59 220

423.54 221

548.45 222

423.54 223

548.45 224

423.54 225

598.51 226

485,59 227 Chiral (S)

485.59 228 Chiral (R)

485.59 229 Chiral (S)

473.55 230 Chiral (R)

473.55 231

522.67 232 Chiral (S)

522.67 233 Chiral (R)

551.51 234 Chiral (S)

551.51 235 Chiral (S)

598.51 236 Chiral (R)

598.51 237

473.6 238

473.6 239 Chiral (S)

417.56 240

500.62 241

530.65 242

522.67 243 Chiral (S)

522.67 244

530.65 245

517.61 246

517.61 247

497.62 248

500.62 249

544.68 250

511.65 251

531.64 252

531.64 253

514.65 254

492.58 255

480.59 256

478.64 257

466.56 258

348.43 259

492.58 260

511.65 261

497.62 262

535.6 263

515.61 264 Chiral (S)

396.5 265 Chiral (S)

426.5 266 Chiral (S)

354.5 267 Chiral (S)

374.5 268 Chiral (S)

380.9 269 Chiral (S)

329.4 270 Chiral (S)

343.4 271 Chiral (S)

360.5 272 Chiral (S)

329.4 273 Chiral (S)

422.6 274 Chiral (S)

457 275 Chiral (S)

458.5 276 Chiral (S)

432.5 277 Chiral (S)

436.6 278 Chiral (S)

410.5 279 Chiral (S)

424.6 280 Chiral (S)

431 281 Chiral (S)

426.5 282 Chiral (S)

410.5 283 Chiral (S)

414.5 284 Chiral (S)

396.5 285 Chiral (S)

431 286 Chiral (S)

441.5 287 Chiral (S)

472.6 288 Chiral (S)

417.6 289 Chiral (S)

440.5 290 Chiral (S)

436.6 291 Chiral (S)

440.5 292 Chiral (S)

457 293 Chiral (S)

467.6 294 Chiral (S)

454.6 295 Chiral (S)

476.6 296 Chiral (S)

459.6 297 Chiral (S)

427.5 298 Chiral (S)

423.5 299-300 Chiral (S)

462.6 301 Chiral (S)

359.5 302 Chiral (S)

422.4 303 Chiral (R)

396.5 304 Chiral (R)

426.5 305 Chiral (R)

354.5 306 Chiral (R)

374.5 307 Chiral (R)

380.9 308 Chiral (R)

329.4 309 Chiral (R)

343.4 310 Chiral (R)

360.5 311 Chiral (R)

329.4 312 Chiral (R)

422.6 313 Chiral (R)

457 314 Chiral (R)

458.5 315 Chiral (R)

432.5 316 Chiral (R)

436.6 317 Chiral (R)

410.5 318 Chiral (R)

424.6 319 Chiral (R)

431 320 Chiral (R)

426.5 321 Chiral (R)

410.5 322 Chiral (R)

414.5 323 Chiral (R)

396.5 324 Chiral (R)

431 325 Chiral (R)

441.5 326 Chiral (R)

472.6 327 Chiral (R)

417.6 328 Chiral (R)

440.5 329 Chiral (R)

436.6 330 Chiral (R)

440.5 331 Chiral (R)

457 332 Chiral (R)

467.6 333 Chiral (R)

454.6 334 Chiral (R)

476.6 335 Chiral (R)

459.6 336 Chiral (R)

427.5 337 Chiral (R)

423.5 338 Chiral (R)

359.5 339 Chiral (R)

422.4

Example 340

[0513]

[0514] Step 1

[0515] To a solution of the product of preparation 14 (100 mg, 0.38mmol, 1.0 equi.) in acetonitrile (5 mL) was added 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (DEC) (87 mg, 0.45 mmol, 1.2equi.), 1-hydroxy-7-azabenzotriazole (HOAt) (62 mg. 0.45 mmol, 1.2equi.), triethyl amine (0.13 mL, 0.94 mmol, 2.5 equi.), and2-aminothiazole (45.5 mg, 0.45 mmol, 1.2 equi.). The reaction solutionwas heated to 80° C. for 18 hours. The reaction was then concentrated invacuo. The product mixture was purified by flash chromatography (20%ethyl acetate in hexane) to yield 112.4 mg (86%) of the product of step1: LC/MS (m/z 347, (M+H)⁺); ¹H NMR (CDCl₃) δ 7.52 (d, 1H), 6.98-7.27 (m,9H), 4.42 (s, 1H), 4.32 (t, 1H), 2.69 (dd, 1H), 1.52 (dd, 1H), 1.16(s,3H).

[0516] Step 2

[0517] To a solution of the product of step 1 (175 mg, 0.5 mmol, 1.0equi.) in THF (5 mL) was added sodium hydride (18 mg, 0.75 mmol, 1.5equi.) and the solution stirred at RT for 1 hour. A solution of methyliodide (0.047 mL, 0.75 mmol, 1.5 equi.) in THF (1 μL) was added and thereaction solution was stirred at RT for 3 hours. The solution wasquenched with ethyl acetate. The organic layer was washed with water,saturated sodium chloride, dried with magnesium sulfate and concentratedin vacuo. Purification of the crude product mixture by flashchromatography (10% ethyl acetate in hexane) yielded 141.7 mg (78%) ofExample 340: LC/MS (m/z 361 (M+H)⁺); ¹H NMR (CDCl₃) δ 6.41-7.12 (m, 8H),4.67 (s, 1H), 4.3 (t, 1H), 3.63 (s, 3H), 3.0 (dd, 1H), 1.49 (dd, 1H),1.07 (s, 3H).

Examples 341 to 343

[0518] In a similar manner the following compounds were prepared. MS:(M + H = Example Structure MW +1) 341

436.58 342

486.64 343

562.74

Examples 344 to 346

[0519]

[0520] Step 1

[0521] To a solution of the product of Preparation 14, (4.72 mmol, 1.25g) in acetonitrile (20 mL) was added1-[3-(dimethylamino)propyl-3-ethylcarbodiimide hydrochloride (EDCI),(5.66 mmol, 1.09 g), 1-hydroxy-7-azabenzotriazole (HOAt), (5.66 mmol,0.77 g), triethylamine (11.8 mmol, 1.20 g) and the product ofpreparation 11 (5.66 mmol, 1.41 g). The resulting mixture was heated to80° C. for 20 h, cooled and concentrated in vacuo. The residue waschromatographed on silica gel (eluted with 15% ethyl acetate in hexane)to give 1.80 g (Y: 77%) of Example 344. MS (E+) m/z: 494 (MH⁺).

[0522] Step 2

[0523] To a solution of Example 344 (3.44 mmol, 1.70 g) in EtOH (30 mL)was added 10 N NaOH (2.0 mL). The resulting mixture was heated to 75° C.for 2.5 h, cooled and diluted with an excess of 1 N HCl. The mixture wasthen extracted with dichloromethane (3×100 mL), dried over Na₂SO₄ andconcentrated under vacuo to give 1.40 g (Y: 88%) of Example 345. MS (E+)m/z: 467 (MH⁺).

[0524] Step 3

[0525] To a solution of Example 345 (0.038 mmol, 18.0 mg) intetrahydrofuran (1.0 mL) was added1-[3-(dimethylamino)propyl-3-ethylcarbodiimide hydrochloride (EDCI),(0.046 mmol, 8.9 mg), 1-hydroxy-7-azabenzotriazole (HOAt), (0.046 mmol,6.3 mg), triethylamine (0.046 mmol, 5.6 mg) and aniline (0.046 mmol, 4.3mg). After 20 h at room temperature the product was purified using solidphase extraction cartridges (500 mg 1/1 high load, SCX strong cationexchanger/SAX strong anion exchanger) from United Chemical Technologies,Inc. After conditioning the cartridge with MeOH (2×1.5 mL) the crudereaction mixture was loaded on to the cartridge. The cartridge was thenwashed with MeOH (2×1.5 mL) to afford two fractions of the titlecompound. These fractions were combined & concentrated and then purifieda second time using solid phase extraction cartridges (500 mg SAX stronganion exchanger) to remove any HOAt that was still present. Afterconditioning the cartridge with MeOH (2×1.5 mL) the crude product wasloaded on to the cartridge. The cartridge was then washed with MeOH(1×1.5 mL) and the eluent was collected. The resultant eluent wasevaporated in vacuo to afford 7.70 mg (37%) of Example 346. MS (E+) m/z:542 (MH⁺).

Examples 347 to 563

[0526] In a similar manner the Examples 347-563 were prepared. ChiralMS: (M + H = Example Compounds Structure MW +1) 347

555.7 348

555.7 349

569.73 350

493.6 351

547.7 352

561.8 353

571.7 354

571.7 355

571.7 356

590.2 357

585.7 358

585.7 359

590.2 360

585.7 361

523.7 362

569.7 363

604.2 364

599.8 365

599.8 366

604.2 367

599.8 368

590.2 369

604.2 370

617.8 371

583.8 372

523.7 373

519.7 374

535.7 375

535.7 376

581.7 377

555.7 378

576.7 379

599.8 380

626.8 381

583.8 382

638.6 383

629.8 384

559.7 385

652.6 386

551.7 387

613.8 388

597.8 389

597.8 390

627.8 391

601.7 392

533.7 393

575.8 394

561.8 395

561.8 396

545.7 397

591.7 398

549.7 399

561.7 400

570.7 401

542.7 402

542.7 403

556.7 404

536.7 405

570.7 406

610.8 407

548.7 408

624.8 409

550.7 410

570.7 411

584.7 412

562.7 413

559.7 414

493.6 415

547.7 416

561.8 417

541.7 418

571.7 419

571.7 420

571.7 421

590.2 422

585.7 423

585.7 424

590.2 425

585.7 426

523.7 427

569.7 428

604.2 429

599.8 430

599.8 431

604.2 432

599.8 433

590.2 434

604.2 435

617.8 436

583.8 437

523.7 438

535.7 439

581.7 440

555.7 441

576.7 442

608.8 443

599.8 444

569.7 445

561.7 446

583.8 447

638.6 448

629.8 449

559.7 450

652.6 451

652.6 452

551.7 453

601.7 454

597.8 455

597.8 456

627.8 457

601.7 458

533.7 459

575.8 460

561.8 461

561.8 462

545.7 463

549.7 464

626.8 465

570.7 466

542.7 467

556.7 468

556.7 469

536.7 470

570.7 471

610.8 472

548.7 473

624.8 474

550.7 475

562.7 476

559.7 477

481.58 478

467.55 479

572.69 480

572.69 481

602.72 482

606.1 483

587.7 484

589.7 485

631.8 486

601.7 487

601.7 488

585.7 489

541.68 490

571.7 491

571.7 492

601.73 493 Chiral (S)

571.7 494 Chiral (S)

606.1 495 Chiral (S)

587.7 496 Chiral (S)

589.7 497 Chiral (S)

631.8 498 Chiral (S)

601.7 499 Chiral (S)

601.7 500 Chiral (S)

585.7 501

576.1 502

591.7 503

576.1 504

576.1 505

610.6 506

610.6 507

617.8 508

610.6 509

610.6 510

581.7 511

548.7 512

677.7 513

549.7 514

542.7 515

582.7 516

617.7 517

563.7 518

562.7 519

617.1 520

598.8 521

577.7 522

587.8 523

585.7 524

573.7 525

585.7 526

587.8 527

609.7 528

555.7 529

569.7 530

587.8 531

562.7 532

565.7 533

606.1 534

545.7 535

572.7 536 Chiral (S)

466.56 537 Chiral (S)

480.59 538 Chiral (S)

572.7 539 Chiral (S)

587.8 540 Chiral (S)

585.7 541 Chiral (S)

573.7 542 Chiral (S)

585.7 543 Chiral (S)

582.7 544 Chiral (S)

576.1 545 Chiral (S)

571.7 546 Chiral (S)

533.7 547 Chiral (S)

542.7 548 Chiral (S)

582.7 549 Chiral (S)

562.72 550 Chiral (R)

606.15 551 Chiral (R)

566.7 552 Chiral (R)

572.7 553 Chiral (R)

562.7 554 Chiral (R)

587.8 555 Chiral (R)

585.7 556 Chiral (R)

573.7 557 Chiral (R)

585.7 558 Chiral (R)

582.7 559 Chiral (R)

576.1 560 Chiral (R)

571.7 561 Chiral (R)

533.7 562 Chiral (R)

542.7 563 Chiral (R)

582.7

Example 564

[0527]

[0528] Step 1

[0529] From the frozen vegetative stock culture of Streptomyces griseusATCC 10137, 2 ml was used to inoculate 100 ml of F7 medium contained thefollowing per liter of deionized water: dextrose, 10 g; yeast extract,10 g; malt extract, 10 g; peptone, 1 g, in a 500 ml flask (pH wasadjusted to 7 before sterilization at 120° C. for 30 minutes). Theculture was incubated for 3 days at 28° C. on a rotary shaker operatingat 250 rpm. Two ml of this culture was used to inoculate each of twelve500-ml flasks containing 100 ml of F7 medium. The flasks were incubatedat 28° C. on a rotary shaker operating at 250 rpm for 17 hours. Eight mgof Preparation 16 g S-isomer (97.9% ee) in 0.32 ml DMF was added to eachflask. The flasks were then returned to the shaker and incubated foradditional 9.5 hours at 28° C. and 250 rpm. The culture was pooled andsubjected to sonication for total of 5 min. with a High IntensityUltrasonic Processor (Model: VCX600, Sonics & Material Inc.) equippedwith a microtip, at 40% out put. The resulting mixture was extractedwith 600 ml ethyl acetate and the ethyl acetate extract was evaporatedto dryness. The residue was dissolved in 2 ml of acetoniltrile andsubjected to preparative HPLC with a YMC ODS-A column (30 mm ID X 100 mmlength, 5 g particle size). Elution flow rate was 30 ml/min. In eachrun, sample (0.5 to 1 ml) was loaded onto the column at water (solventA)-acetonitrile (solvent B) 90/10 v/v and separated using the followinggradient program: 10% B, 3 min; 10% to 35% B linear gradient, 1 min; 35%B, 9 min; 35% to 60% B linear gradient, 1 min; 60% B, 4 min; 60% to 90%B linear gradient, 1 min; 90% B, 4 min. Detection (UV) was at 210 nm.The fractions containing BMS-585157 was eluted between 18 to 19 minutes.The BMS-585157 fractions were pooled and evaporated in vacuo to a smallvolume, then was lyophilized. A total of 60 mg of BMS-585751 wasobtained as light yellow solid (yield, 62.5%). The reaction andpurification were monitored by analytical HPLC with a Hewlett Packard1100 Series Liquid Chromatograph using an YMC Packed ODS-AQ column, 4.6mm i.d.×15 cm 1. A gradient system of 1 mM HCl in water (solvent A) andacetonitrile (solvent B) was used: 70% to 90% B linear gradient, 5 min;90% B, 1.5 min; 90% to 70% linear gradient, 0.5 min. The flow rate was1.2 ml/min and UV detection was at 210 nm. Retention time for startingcompound and product was 5.16 and 2.76 min, respectively. ¹H-NMRObserved Chemical Shifts (relative to CD₃CN signal δ 1.94): δ 7.33 (3H,m), 7.21 (1H, m), 7.15 (2H, m), 7.09 (2H, m), 4.61 (1H, dd, J_(t)=5.8Hz, J₂=3.2 Hz, CH-3), 4.40 (1H, s, CH-11), 4.32 (1H, d, J=3.5 Hz, CH-4),3.51 (3H, s, CH₃-19), 2.90 (1H, d, J=6.0 Hz, OH), 0.93 (1H, s, CH₃-18).1H-¹H NOE Observed NOE: CH-4 and OH (when CH-3 was irradiated); CH-11and OH (when CH₃-18 was irradiated). MS:+c APCI (m/z): 312 ([M+H₂O]+),294, 277.

[0530] Step 2

[0531] To a solution of the product of step 1 (0.079 mmol, 23 mg) inMeOH (2 mL) was added sodium hydroxide (400 μL of 1 N NaOH, 0.4 mmol).After 4 hours at 75° C. and 16 hours at RT the reaction mixture wasquenched with 1N HCl (3 mL) and extracted with dichloromethane (3×30mL). The organic phases were dried over Na₂SO₄ and concentrated in vacuoto give 19.6 g (Y: 89%) of the product of step 2.

[0532] Step 3

[0533] To a solution of the product of step 2 (0.070 mmol, 19.6 mg) inacetonitrile (1.0 mL) was added1-[3-(dimethylamino)propyl-3-ethylcarbodiimide hydrochloride (EDCI),(0.084 mmol, 16 mg), 1-hydroxy-7-azabenzotriazole (HOAt), (0.084 mmol,11.5 mg), triethylamine (0.175 mmol, 17.7 mg) and Preparation 1a (0.086mmol, 21 mg). The resulting mixture was heated to 80° C. for 20 h,cooled and diluted with MeOH (1.0 mL). The diluted reaction mixture wasthen purified by preparative HPLC to afford the TFA salt of the titlecompound. The product was then neutralized using a solid phaseextraction cartridge (500 mg high load, SCX strong cation exchanger fromUnited Chemical Technologies, Inc). After conditioning the cartridgewith MeOH (2×1.5 mL) the product was loaded on to the cartridge. Thecartridge was then washed with MeOH (2×1.5 mL), followed by a 2N NH₃ inMeOH solution to afford 18.8 mg (55%) of Example 564. MS (E+) m/z: 507(MH⁺).

Example 565

[0534]

[0535] To a solution of Example 178 (20.0 mg, 0.04 mmol, 1.0 equi.) indichloromethane (5 mL) at 0° C., was added a solution of borontribromide in dichloromethane (1M, 0.20 mL, 0.20 mmol, 5 equi.). Thereaction solution was stirred at 0° C. for 3 hours, and let warmed up toroom temperature and let stirred at room temperature overnight. The nextday, the reaction solution was quenched with methanol in an ice bath.The crude product mixture was purified by reversed phased PREP HPLC,followed by neutralization with cation exchange SPE, to yield 5.4 mg(28% yield) of Example 565: LC/MS (m/z 489, (M+H)⁺).

Examples 566 to 567

[0536] Examples 566 to 567 in the table below were prepared in a similarmanner from the corresponding methyl ethers. MS: (M + H = Example 1Structure MW + 1) 566

488.61 567

488.61

Examples 568 to 569

[0537]

[0538] Step 1

[0539] To a solution of the product of preparation 16d (2.45 mmol, 650mg) in THF (10.0 mL) at −78° C. was added lithium diisopropylamide (2.94mmol, 1.47 ml of a 2 M solution in heptane/THF/ethyl benzene) dropwise.After 1 hour, bromoacetonitrile (3.68 mmol, 440 mg) in THF (0.70 mL) wasadded dropwise. The mixture was allowed to warm to RT. After 16 hoursthe reaction mixture was quenched with 1N HCl (30 mL) and extracted withdichloromethane (3×30 mL). The organic phases were concentrated in vacuoand the residue chromatographed on silica gel (eluted with 20% ethylacetate in hexane) to give 510 mg (Y: 69%) of the product of step 1.

[0540] Step 2

[0541] To a solution of the product of step 1 (1.68 mmol, 510 mg) in THF(3.4 mL) was added lithium hydroxide (1.7 mL of 5N LiOH). After 20 hoursat 70° C. the reaction mixture was quenched with 1N HCl (30 mL) andextracted with dichloromethane (3×30 mL). The organic phases were driedover Na₂SO₄ and concentrated in vacuo to give 410 mg (Y: 84%) theproduct of step 2

[0542] Step 3

[0543] To a solution of the product of step 2 (0.45 mmol, 130 mg) indichloromethane (2.0 mL) was added oxalyl chloride (0.54 mmol, 0.28 mLof a 2 N solution in dichloromethane) and DMF (2 drops). After 1 hour atRT the reaction mixture is concentrated in vacuo and then redissolved indichloromethane (1.0 mL). To the resulting mixture is then addedtriethylamine (0.54 mmol, 0.075 mL) and methylamine (0.90 mmol, 0.45 mLof a 2 M solution in THF). After 2 hours the reaction mixture wasquenched with saturated sodium bicarbonate solution, extracted bydichloromethane (3×30 mL), dried over Na₂SO₄ and concentrated undervacuo to give 53 mg (Y: 39%) of Example 568.

[0544] Step 4

[0545] To a solution of the product of step 3 (0.132 mmol, 40 mg) inmethanolic ammonia (7.0 mL) was added 5% rhodium on alumina (100 mg).The reaction mixture was then allowed to hydrogenate at 55 psi of H₂ ina Parr apparatus. After 20 hours the reaction mixture was filteredthrough celite and concentrated in vacuo to give 40 mg (Y: 99%) ofExample 569.

Examples 570 to 572

[0546] In a similar manner the Examples 570 to 572 were prepared. MS:(M + H = Example Structure MW + 1) 570

291.4 571

360.48 572

486.64

Example 573

[0547]

[0548] Step 1

[0549] To a solution of the product of preparation 16d (3.90 mmol, 1.03g) in THF (8.0 mL) and TMEDA (1.0 mL) at −78° C. was added lithiumdiisopropylamide (4.69 mmol, 2.35 ml of a 2 M solution inheptane/THF/ethyl benzene) dropwise. After 1 hour the reaction mixturewas saturated with ethylene oxide gas. The reaction mixture was thenwarmed to RT over 3 hours, quenched with 1N HCl (30 μL) and extractedwith dichloromethane (3×30 mL). The organic phases were concentrated invacuo and the residue chromatographed on silica gel (eluted with 10%ethyl acetate in hexane) to give 220 mg (Y: 22%) of the product of step1.

[0550] Step 2

[0551] To a solution of the product of step 1 (0.471 mmol, 130 mg) indichloromethane (8.0 mL) under nitrogen at 0° C. was addedtrimethylaluminum (3.77 mmol, 1.88 ml of a 2 M solution in toluene). Thereaction mixture was allowed to stir at 0° C. for 20 min and then at RTfor 1 h. 2-Aminothiazole (3.77 mmol, 377 mg) in dichloromethane (5.0 mL)was then added. After 16 hours at reflux the reaction mixture isquenched with 1N HCl (30 mL) and extracted with dichloromethane (3×30mL). The organic phases were concentrated in vacuo and the residuechromatographed on silica gel (eluted with 5% methanol indichloromethane) to give 91 mg (Y: 51%) of Example 573. (E+) m/z: 376(MH⁺).

Examples 574 to 575

[0552]

[0553] Step 1

[0554] To a solution of Example 241 (80 mg, 0.15 mmol) in methanol (5mL) was added a sodium hydroxide solution (1.0 mL) (solution is 1:1 of50% NaOH and water). The reaction solution was heated to 60° C. for 5hours. The solution was cooled and quenched with HCl (6N). The productwas extracted with ethyl acetate (3×). The combined organic extractswere dried with anhydrous magnesium sulfate and concentrated in vacuo togive 68 mg (87% yield) of Example 574. LC/MS (m/z 517, (M+H)⁺).

[0555] Step 2

[0556] To a solution of the product of step 1 (20 mg, 0.038 mmol, 1.0equi.) in acetonitrile (2 mL) was added 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (DEC) (8.9 mg, 0.046 mmol, 1.2equi.), 1-hydroxy-7-azabenzotriazole (HOAt) (6.3 mg. 0.046 mmol, 1.2equi.), triethylamine (0.013 mL, 0.097 mmol, 2.5 equi.), and ethylamine(2.1 mg, 0.046 mmol, 1.2 equi.). The reaction solution was heated to 80°C. for 18 hours and followed by concentrated in vacuo. The productmixture was purified by reversed phased PREP HPLC, followed byneutralization with cation exchange SPE, to yield 3.1 mg (14%) ofExample 575: LC/MS (m/z 544, (M+H)⁺); ¹H NMR (CDCl₃) δ 8.22 (m, 1H),7.89(m, 2H), 7.60 (d, 1H), 7.14-7.53 (m, 11H), 7.03 (s, 1H), 4.46 (s,1H), 3.69 (q, 2H), 2.85 (d, 1H), 1.83 (d, 1H), 1.36 (t, 3H), 1.12 (s,3H).

Examples 576 to 578

[0557] In a similar manner the Examples 576 to 578 were prepared. MS:(M + H = Example Structure MW + 1) 576

581.7 577

598.77 578

585.73

Example 579

[0558]

[0559] To a mixture of Example 240 (28 mg, 0.056 mmol, 1.0 equi.) andethylamine (3.0 mg, 0.067 mmol, 1.2 equi.) in methanol (2 mL, 1.0%acetic acid) was added sodium cyanoborohydride (3.5 mg, 0.056 mmol, 1.2equi.). The solution was stirred at room temperature for 18 hours. Thecrude product mixture was purified by reversed phase PREP HPLC, followedby neutralization with cation exchange SPE, to yield 3.8 mg (13%) ofExample 579: LC/MS (m/z 530, (M+H)⁺); ¹H NMR (CDCl₃) δ 8.25 (m, 1H),7.87 (m, 2H), 7.62 (d, 1H), 7.51 (m, 3H), 7.06-7.52 (m, 7H), 7.06 (s,1H), 4.40 (s, 1H), 3.7 (s, 2H), 2.99 (q, 2H), 2.60 (d, 1H), 1.58 (d,1H), 1.28 (t, 3H), 1.19 (s, 3H).

Example 580

[0560] In a similar manner the Example 580 was prepared. MS: (M + H =Example Structure MW + 1) 580

571.75

Example 581

[0561]

[0562] Example 252 (25 mg, 0.05 mmol) was dissolved in a solution ofethanol (5 mL) and hydrochloric acid (concentrated, 0.25 mL) at roomtemperature. Zinc dust (20 mg) was added in and the reaction solutionwas stirred at room temperature for 24 hours. The reaction was quenchedwith sodium bicarbonate solution (10%) and ethyl acetate. The organicphase was washed with 1N sodium hydroxide solution, dried andconcentrated in vacuo to give the crude product mixture. The product waspurified by PREP HPLC, followed by cation exchange SPE to give 4.1 mg(16% yield) of Example 581: MS (m/z 502 (M+H)⁺).

Example 582

[0563]

[0564] To a solution of Example 112 (33 mg, 0.070 mmol) in 1.50 mLanhydrous diethyl ether at room temperature was added 0.18 mL of a 1.0Msolution of lithium aluminum hydride in THF (0.180 mmol, 2.6 eq). Afterstirring at room temperature for 3 h an additional 0.18 mL lithiumaluminum hydride solution (0.180 mmol, 2.6 eq) was added to push thereaction further. The mixture was allowed to stir for 48 h at rt, andquenched by adding 0.15 mL methanol dropwise, then 0.15 mL water, then20 mL saturated aqueous KOH. Extracted 2×30 mL ethyl acetate. Dried oversodium sulfate. Concentrated under vacuum. Purified the crude materialusing prep HPLC. Free-based the product by passing through a basic SCXcartridge using methanol as the eluent. Removal of the solvent afforded2.5 mg of Example 582 as a solid white film (8%) LC/MS (m/z 459,(M+H)⁺).

Example 583

[0565]

[0566] Step 1: 7-methoxy-2-methyl-quinolinyl-4-boronic acid

[0567] To a solution of 4-bromo-7-methoxy-2-methyl-quinoline (700 mg,2.8 mmol), prepared according to a known procedure (Reference: Abe, Y.et. al. J. Med. Chem. 1998, 41, 4062-4097), in THF (15 mL) at −78° C.were added triisopropyl borate (1.3 mL, 5.6 mmol) and t-butyllithium(1.7 M, 5.0 mL). The solution was then slowly warmed to room temperatureand kept stirring overnight. Next morning, the solution was quenchedwith 1N HCl (1.5 mL) and the solid was thus obtained after decantingTHF. The solid was dissolved in MeOH and diluted with CH₂Cl₂. Thesolution was filtered and the filtrate was concentrated to provide7-methoxy-2-methyl-quinolinyl-4-boronic acid (560 mg, 90%). MS (ESI)(M+1)=218.26.

[0568] Step 2:4-(5-bromo-2-nitro-1H-imidazol-4-yl)-7-methoxy-2-methyl-quinoline

[0569] To a solution of the boronic acid from Step 1 (560 mg, 2.6 mmol)and 4,5-dibromo-2-nitro-1H-imidazole (380 mg, 1.4 mmol), preparedaccording to a known procedure (Reference: Palmer, B. D. et. al. J.Chem. Soc. Perkin Trans 1, 1989, 95-99), in 50 mL of THF was added 20 mLof sat. K₂CO₃. To this solution was bubbled a flow of N₂ for 30 minutesand then 200 mg of tetrakis(triphenylphosphine)palladium(0) (0.17 mmol)was added. The solution was heated at 80° C. overnight. After coolingdown, the solution was diluted with EtOAc and the organic layer wasseparated and washed with brine. The organic layer was dried over MgSO₄.After filtration and concentration, the residue was purified by flashcolumn chromatography to provide the desired4-(5-bromo-2-nitro-1H-imidazol-4-yl)-7-methoxy-2-methyl-quinoline (114mg, 15%). MS (ESI) (M+1)=363.29, 365.29.

[0570] Step 3:4-(7-methoxy-2-methyl-quinolin-4-yl)-1H-imidazole-2-ylamine

[0571] To a solution of the product of Step 2 (114 mg, 0.31 mmol) in 15mL of MeOH was added 100 mg of 10% Pd/C and the solution was purged withH₂. The solution was then stirred under H₂ atmosphere overnight. Afterfiltration and concentration, the desired4-(7-methoxy-2-methyl-quinolin-4-yl)-1H-imidazole-2-ylamine (90 mg, 87%)was obtained as a HBr salt. MS (ESI) (M+1)=255.33.

[0572] Step 4

[0573] Following a similar procedure as described in Example 1, thecoupling reaction of the product of Step 3 (32 mg, 0.095 mmol), and theacid of Preparation 17E (39 mg, 0.12 mmol) provided compound of Example583 (26 mg, 50%). MS (ESI) (M+1)=546.33.

Examples 584 to 586

[0574] In a similar manner to the procedure of Example 583, Examples 584to 586 were prepared from acid of Preparation 17E and the appropriate4-(quinolin-4-yl)-1H-imidazole-2-ylamine or4-isoquinolin-5-yl-1H-imidazol-2-ylamine. The amines were preparedaccording to the procedures described in Steps 1 to 3 of Example 583,i.e. via the Pd-catalyzed coupling reaction of4,5-dibromo-2-nitro-1H-imidazole and the boronic acid derived fromcorresponding bromo-quinoline or bromo-isoquinoline, followed by thehydrogenation reaction. Example Structure 584

585

586

Example 587

[0575]

[0576] A suspension Example 212 (50 mg, 0.091 mmol) and cuprious cyanide(10 mg, 0.11 mmol) in DMF (2 mL) was introduced into a dried heavy wallPyrex tube, flushed with nitrogen and tightly sealed. The tube wasplaced in a microwave (Smith Workstation 300W from Magnetron @ 2.45 GHz)and heated to 200° C. while stirring for 2.25 h. After the tube had cooldown to room temperature, the reaction mixture was diluted withdichloromethane, washed with saturated sodium bicarbonate, dried overmagnesium sulfate, filtered and concentrated in vacuo to provide a brownoil. Flash chromatography (Isco silica gel, 4 g column, 10% ethylacetate/hexane) provided Example 587 as an off-white solid (25 mg, 55%yield): ¹H NMR (CDCl₃) δ 8.67 (bs, NH), 8.36 (d, 1H), 8.32 (d, 1H), 7.95(d, 1H), 7.73 (t, 1H), 7.62-7.69 (m, 2H), 7.26-7.38 (m, 4H), 7.15-7.20(m, 3H), 7.14 (s, 1H), 7.09 (t, 1H), 4.37-4.46 (m, 2H), 2.65 (dd, 1H),1.65 (dd, 1H), 1.18 (s, 3H); HPLC t_(R)=4.2 min.; LC/MS m/z 498 (M+H)⁺.

Examples 588 to 645

[0577] In a similar manner as described in Example 1, Examples 588 to645 were prepared from the coupling of corresponding acids and amines.Preparations of amines or acids not commercially available are describedin the preceding preparations section of this document. All examples inthe table are racemic unless specified otherwise. Examples in the tablewhere one enantiomer predominates or is the sole component, aredesignated as either R or S. Separation of the enantiomers on a chiralcolumn employed procedures described in the preceding preparationssection of this document. MS: Example Chiral (M + H = No. StructureCompounds MW + 1) 588

419.18 589

510.34 590

448.38 591

535.2 592

536.21 593

460.38 594

487.46 595

528.32 596

501.3 597

549.28 598

496.16 599

467.2 600

466.13 601

Chiral (R) 532.29 602

Chiral (S) 532.26 603

Chiral (R) 512.27 604

Chiral (S) 512.24 605

372.09 606

392.04 607

498.24 608

519.27 609

486.07 610

486.06 611

493.07 612

468.13 613

496.13 614

482.09 615

Chiral (R) 536.25 616

Chiral (S) 536.27 617

493.01 618

565.03 619

465.05 620

469.05 621

424.33 622

521.05 623

501.09 624

504.99 625

524.95 626

596 627

451.15 628

508.14 629

488.17 630

548.03 631

551 632

515.18 633

504.13 634

651.11 635

484.17 636

552 637

499.1 638

569 639

495.05 640

506.1 641

Chiral (S) 519.05 642

Chiral (R) 519.01 643

489.07 644

519.19 645

481.34

Example 646

[0578]

[0579] To a solution of Example 178 (100 mg, 0.29 mmol, 1.0 equi.) inacetonitrile (5 mL) was added N-iodosuccinimide (65 mg, 0.29 mg, 1.0equi.). The solution was stirred at room temperature for 2 hours. Thesolution was quenched with saturated sodium bisulfite solution, anddiluted with ethyl acetate. The organic phase was washed with water,dried with sodium sulfate and concentrated in vacuo. Purification of thecrude product mixture by flash chromatography (20% ethyl acetate inhexane) yielded 22.7 mg (16%) of Example 647: LC/MS (m/z 629, (M+H)⁺).

Examples 647 to 648

[0580] In a manner similar to Example 646, Examples 647 to 649 wereprepared. Chiral MS: (M + H = Example Compounds Structure MW + 1) 647

472.35 648 Chiral (S)

472.35 649 Chiral (R)

472.35

What is claimed is:
 1. A compound having below structure:

including all stereoisomers thereof, or a prodrug ester thereof, or apharmaceutically acceptable salt thereof, wherein R is hydrogen, alkyl,alkenyl, alkynyl, alkoxy, aryl, arylalkyl, aryloxy, heteroaryl,cycloheteroalkyl, heteroarylalkyl, cycloheteroalkylalkyl, cycloalkyl,cycloalkylalkyl, cyanoalkyl, aminoalkyl, hydroxyalkyl, aryloxyalkyl, orhydroxyaryl; R^(a) is hydrogen, alkyl, alkenyl, alkynyl, alkoxy, aryl,aryloxy, heteroaryl, cycloheteroalkyl, heteroarylalkyl,cycloheteroalkylalkyl, cyano, halogen, heteroarylaminocarboyl,cycloheteroalkylcarbonyl, cyanoalkyl, alkylaminoalkyl, hydroxyalkyl,hydroxyaryl, aryloxyalkyl, nitro, amino, CHO, CO₂ alkyl, CONR^(e)R^(f),CH₂NR^(g)R^(h), CO₂H, CH₂OH, CH₂NHR^(g), NHCH₂R^(g), NHCHR^(g)R^(h),NHCOR^(e)NHCONR^(e)R^(f) or NHSO₂R^(e); R^(b) is hydrogen, alkyl,alkenyl, alkynyl, alkoxy, aryl, aryloxy, heteroaryl, cycloheteroalkyl,heteroarylalkyl, cycloheteroalkylalkyl, cyano, halogen,heteroarylaminocarbonyl, cycloheteroalkylcarbonyl, cyanoalkyl,alkylaminoalkyl, hydroxyalkyl, nitro, amino, CHO, CO₂ alkyl,hydroxyaryl, aryloxyalkyl, CONR^(i)R^(j), CH₂NR^(k)R^(l), CO₂H, CH₂OH,CH₂NHR^(k), NHCH₂R^(k), NHCH^(k)R^(l), NHCOR^(i), NHCONR^(i)R^(j) orNHSO₂R^(i); where R^(e) and R^(f) are the same or different and areindependently selected hydrogen, aryl, alkyl, alkenyl, alkynyl, alkoxy,amino, alkoxyalkyl, alkylaminoalkyl, dialkylaminoalkyl, heteroaryl,cycloheteroalkyl, heteroarylalkyl, cycloheteroalkylalkyl, cycloalkyl, orcycloalkylalkyl, and R^(e) and R^(f) can be taken together with thenitrogen to which they are attached to form a 5-, 6- or 7-memberedheteroaryl or cycloheteroalkyl ring which contains 1, 2 or 3 heteroatoms which can be N, O or S; R^(g) and R^(h) are the same or differentand are independently selected hydrogen, aryl, alkyl, alkenyl, alkynyl,alkoxy, amino, alkoxyalkyl, alkylaminoalkyl, dialkylaminoalkyl,heteroaryl, cycloheteroalkyl, heteroarylalkyl, cycloheteroalkylalkyl,cycloalkyl, or cycloalkylalkyl, and R^(g) and R^(h) can be takentogether with the nitrogen to which they are attached to form a 5-, 6-or 7-membered heteroaryl ring or cycloheteroalkyl ring which contains 1,2 or 3 hetero atoms which can be N, O or S; R^(i) and R^(j) are the sameor different and are independently selected hydrogen, aryl, alkyl,alkenyl, alkynyl, alkoxy, amino, alkoxyalkyl, alkylaminoalkyl,dialkylaminoalkyl, heteroaryl, cycloheteroalkyl, heteroarylalkyl,cycloheteroalkylalkyl, cycloalkyl, or cycloalkylalkyl, and R^(i) andR^(j) can be taken together with the nitrogen to which they are attachedto form a 5-, 6-or 7-membered heteroaryl ring or cycloheteroalkyl ringwhich contains 1, 2 or 3 hetero atoms which can be N, O or S; R^(k) andR^(l) are the same or different and are independently selected hydrogen,aryl, alkyl, alkenyl, alkynyl, alkoxy, amino, alkoxyalkyl,alkylaminoalkyl, dialkylaminoalkyl, heteroaryl, cycloheteroalkyl,heteroarylalkyl, cycloheteroalkylalkyl, cycloalkyl, or cycloalkylalkyl,and R^(k) and R^(l) can be taken together with the nitrogen to whichthey are attached to form a 5-, 6- or 7-membered heteroaryl ring orcycloheteroalkyl ring which contains 1, 2 or 3 hetero atoms which can beN, O or S; R^(c) and R^(d) are the same or different and areindependently selected from hydrogen, alkyl, alkenyl, alkynyl, alkoxy,aryl, hydroxy, aryloxy, heteroaryl, cycloheteroalkyl, heteroarylalkyl,cycloheteroalkylalkyl, hydroxyaryl, or aryloxyalkyl; R^(c) and R^(d) mayoptionally be taken together with the carbon to which they are attachedto form a 3- to 7-membered ring which may optionally include an O atomor an N atom; Z is CONR¹R² or CH₂NR¹R² wherein R¹ and R² are the same ordifferent and are independently selected from hydrogen, alkyl, alkenyl,alkynyl, alkoxy, cycloalkyl, cycloalkylalkyl, aryl, heteroaryl,heteroarylalkyl, cycloheteroalkyl, cycloalkenyl, monoalkylaminoalkyl,dialkylaminoalkyl, cycloheteroalkylalkyl, hydroxyaryl, aryloxyalkyl,alkoxyalkyl or hydroxyalkyl; the A ring represents a saturated,partially saturated or unsaturated 6-membered carbocyclic orheterocyclic ring; and the B ring represents a saturated, partiallysaturated or unsaturated 6-membered carbocyclic or heterocyclic ring;With the following provisos: I. provided that where Z is CONR¹R² and (a)R is CH₃ or H and R^(a), R^(b), R^(c) and R^(d) are each hydrogen, or(b) R^(a) and R^(b) are each hydrogen and one of R^(c) and R^(d) isalkyl, then (1) at least one of R¹ and R² is heteroaryl,heteroarylalkyl, cycloheteroalkyl or cycloheteroalkylalkyl, but wherethe heteroaryl is unsubstituted

or unsubstituted

or the heteroarylalkyl is unsubstituted

, then the other of R¹ and R² is other than hydrogen, and/or the A ringincludes a hetero atom and/or the B ring includes a hetero atom; or (2)where one of R¹ and R² is phenyl which is substituted with alkyl,hydroxy, halo, C₁-C₂-alkoxycarbonyl or nitro, then (a) the phenyl mustbe substituted with at least one other group other than hydrogen, alkyl,hydroxy, halo, C₁, —C₂-alkoxycarbonyl or nitro, except that the phenylmay be substituted with two or more halo atoms, and/or two or morehydroxy groups and/or (b) the other of R¹ and R² is other than hydrogenand/or (c) the A ring includes a hetero atom and/or the B ring includesa hetero atom; (3) where one of R¹ and R² is phenyl substituted withC₁-C₂ alkoxy, the phenyl cannot be substituted with a second C₁-C₂alkoxy or the other of R¹ and R² is other than hydrogen; or (4) where atleast one of R¹ and R² is hydrogen, unsubstituted alkyl, alkenyl,cycloalkyl, alkylcycloalkyl, cycloalkenyl, alkylcycloalkenyl,alkylphenyl, monoalkylaminoalkyl, dialkylaminoalkyl, arylalkyl, aryl,alkoxyalkyl or hydroxyalkyl then (a) the other of R¹ and R² is otherthan hydrogen, unsubstituted alkyl, alkenyl, cycloaklyl,alkylcycloalkyl, cycloalkenyl, alkylcycloalkenyl, alkylphenyl,monoalkylaminoalkyl, dialkylaminoalkyl, arylalkyl, aryl, alkoxyalkyl orhydroxyalkyl and/or (b) at least one of R^(a), R^(b), R^(c) and/or R^(d)is other than hydrogen and/or (c) R is other than hydrogen or C₁-C₂alkyl and/or (d) the A ring includes a hetero atom and/or the B ringincludes a hetero atom; and II. provided that where Z is CH₂NR¹R² and/orwhere at least one of R¹ and R² is hydrogen, alkyl, alkenyl, cycloalkyl,alkylcycloalkyl, phenyl, alkylphenyl, phenylalkyl, monoalkylaminoalkyl,dialkylaminoalkyl, arylalkyl, aryl, alkoxyalkyl, hydroxyalkyl,heteroaryl which is pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl orimidazolinyl, or cycloheteroalkyl which is 4,5-dihydro-imidazol-2-yl,piperidinyl or piperazinyl, then (a) the other of R¹ and R² is otherthan hydrogen, alkyl, alkenyl, cycloalkyl, alkylcycloalkyl, phenyl,alkylphenyl, phenylalkyl, monoalkylaminoalkyl, dialkylaminoalkyl,arylalkyl, aryl, alkoxyalkyl, or hydroxyalkyl, and/or (b) at least oneof R^(a), R^(b), R^(c) and/or R^(d) is other than hydrogen or C₁₋₂alkyl, and/or (c) R is other than hydrogen or C₁-C₂ alkyl and/or (d) theA ring includes a hetero atom and/or the B ring includes a hetero atom,and/or (e) one of R^(c) and R^(d) is other than hydroxyalkyl.
 2. Thecompound as defined in claim 1 wherein the A ring has the structure

and the B ring has the structure

wherein X₁, X₂, X₃ and X₄, are the same or different and areindependently selected from CH, CH₂, CHR¹⁵, CR¹⁶, CR¹⁶R¹⁷, N, NH, NR¹⁸,O or S, and X₅, X₆, X₇ and X₈ are the same or different and areindependently selected from CH, CH₂, CHR¹⁹, CR²⁰, CR²⁰R²¹, N, NH, NR²²,O or S, wherein R¹⁵, R¹⁶, R¹⁷, R¹⁸, R¹⁹, R²⁰, R²¹ and R²² are the sameor different and are independently selected from hydrogen, alkyl, aryl,cycloalkyl, heteroaryl, and cycloheteroalkyl, wherein each of said Aring and said B ring contains at most two nitrogen ring atoms, at mosttwo oxygen ring atom and at most one sulfur ring atom.
 3. The compoundas defined in claim 1 having the structure


4. The compound as defined in claim 1 having the structure

where R is H or alkyl; R^(a) is selected from H, CN, NO₂, NH₂, CHO, CO₂alkyl, CONR^(e)R^(f) or CH₂NR^(g)R^(h); and R^(b) is selected from H,CN, NO₂, NH₂, CHO, CO₂ alkyl, CONR^(i)R^(j) or CH₂NR^(k)R^(l).
 5. Thecompound as defined in claim 1 having the structure

where R is H, CH₃ or C₂H₅ and R^(c) is H or OH, and one of R¹ and R² isheteroaryl.
 6. The compound as defined in claim 5 wherein one of R¹ andR² is

where R^(m) is selected from H, alkyl, aryl, heteroaryl, halo, or alkoxyand R^(o) is H or alkyl.
 7. A compound having the structure

where X is aryl or alkyl;

where X is aryl;

where X is aryl;

where X is aryl, alkyl, heteroaryl or halo and R is alkyl;

where X_(a) is aryl, heteroaryl or heteroarylalkyl,

where R_(a) is alkoxycarbonyl (CO₂ alkyl), nitro, cyano, or hydrogen;R^(b) is hydrogen, CO₂ alkyl, nitro, cyano, formyl,cycloheteroalkylcarbonyl, alkylaminoalkyl or amino, X is hydrogen, alkylor halo;


8. The compound as defined in claim 7 having the structure

where X is 1-naphthyl, 1-(4-methyl)naphthyl, 1-(4-fluoro)naphthyl,1-(6-methoxy)naphthyl, phenyl, t-butyl,

where X is 1-naphthyl

where X=1-naphthyl

where R is CH₃ or C₂H₅ and X is phenyl, t-butyl, 1-naphthyl,1-(4-fluoro)naphthyl, benzthiophen-3-yl, 1-(4-methyl)naphthyl,1-(2-methoxy)naphthyl, 1-(6-methoxy)naphthyl, 3-fluorophenyl,4-fluorophenyl, 3-methylphenyl, 2-chlorophenyl, 1-(4-methoxy)naphthyl,1-(4-bromo)naphthyl, 1-(4-iodo)naphthyl, 5-anthracenyl, 1-anthracenyl,4-quinolin-1-yl, 2-quinolin-1-yl, 1-(4-cyano)naphthyl, 5-iodo,4-benzthiophenyl, 1-(2-hydroxy)naphthyl, 1-(6-hydroxy)naphthyl,1-(4-hydroxy)naphthyl

where X_(a) is phenyl, 3-methoxyphenyl, 4-methoxyphenyl,2,5-dimethoxyphenyl, 3,5-dimethoxyphenyl, 3-pyridyl, 2-(4-pridyl)ethyl,2-(4-imidazolyl)ethyl, 3-chloro-4-methoxyphenyl,3-hydroxy-4-methoxyphenyl, 3-fluoro-4-methoxyphenyl,3,4,5-trimethoxyphenyl, 3,4-dimethoxyphenyl, 4-methyl-3-methoxyphenyl,3-methoxyphenyl, 3,5-dimethoxyphenyl, 2,3-dimethoxyphenyl,4-chlorophenyl, 2-naphthyl, 3-chlorophenyl, 3,4-dichlorophenyl,4-azidophenyl, 2,4-dimethoxyphenyl, 3-ethoxyphenyl,3-(methylthio)phenyl, 4-(methylthio)phenyl, 3-(acetylenyl)phenyl,4-methoxy-3-pyridyl, 3-cyanophenyl, 2-methyl-4-methoxyphenyl,3-azidophenyl, 3-methyl-isothiazolyl, 1-methyl-pyrazol-5-yl,5-trifluoromethyl-1,3,4-thiadiazol-2-yl

R^(a) R^(b) X CH₃OOC— H H Nitro H H Cyano H H CH₃OOC— H Methyl Nitro HMethyl Cyano H Methyl H CH₃OOC— H H Nitro H H Cyano H H formyl H HCO—(N-morpholine) H H —CH2—NH-Ethyl H H —CH2—(N-morpholine) H H NitroMethyl H Cyano Methyl H NH2 Methyl H Nitro F H Cyano F H Cl H H Cl F HCl Methyl H Br F H Br Methyl H CH3 H H CH3 F H CH3 Methyl

CH₃OOC— H H Nitro H H Cyano H H CH₃OOC— H Methyl Nitro H Methyl Cyano HMethyl H CH₃OOC— H H Nitro H H Cyano H H formyl H H CO—(N-morpholine) HH —CH2—NH-Ethyl H H —CH2—(N-morpholine) H H Nitro Methyl H Cyano MethylH NH2 Methyl H Nitro F H Cyano F H Cl H H Cl F H Cl Methyl H Br F H BrMethyl H CH3 H H CH3 F H CH3 Methyl

H H

H nitro

H H

H nitro

H H

H nitro

H H

H nitro

Q=N, Y=CH or Q=CH, Y=N


9. A compound having the structure

where R is CH₃, C₂H₅ or 2-hydroxyethyl, and one of R¹ and R² is H andthe other of R¹ and R² is benzothiazol-2-yl, alkylbenzothiazol-2-yl,alkoxybenzothiazol-2-yl, halobenzothiazol-2-yl, thiazol-2-yl,4-(1-naphthyl)thiazol-2-yl, 2-quinolin-1-yl, or a thiazole which isoptionally substituted with heteroarylthio, heteroaryl, dialkyl, alkyl,aryl, where the aryl may be optionally substituted with halo, alkyl,nitro, hydroxy, alkoxy, dialkoxy, carboxy, alkylaminocarbonyl,arylaminocarbonyl, hydroxyalkylaminocarbonyl, cycloheteroalkylcarbonyl,alkoxyalkylaminocarbonyl or heteroarylaminocarbonyl; with the provisothat where one of R¹ and R² is thiazol-2-yl, then R is C₂H₅ or2-hydroxyethyl.
 10. The compound as defined in claim 9 having thestructure

where X is H, 6-CH₃, 4-CH₃O, 6-Cl or 6-F; or

where X is 4,5-dimethyl, 5-chloro, 4-methyl, 5-methyl, 4-phenyl,4-(1-naphthyl), 4-(2-naphthyl), 4-(4-fluoronaphth-1-yl),4-(4-methylnaphth-1-yl), 4-(3-nitrophenyl), 4-(6-hydroxynaphth-1-yl),4-[(1,2,4-triazol-5-yl)thio]methyl, 4-benzoic acid,4-(4-bromonaphth-1-yl), 4-(N-ethyl)benzamide,4-(N-2-methoxyphenyl)benzamide, 4-(N-methyl-N-2-hydroxyethyl)benzamide,4-(N-(pyrrolidinyl)benzamide, 4-(N-mopholinyl)benzamide,4-(N-phenyl-N-methyl)benzamide, 3-(N-ethyl)benzamide,3-(N-2-methoxyphenyl)benzamide, 3-(N-2-methoxyethyl)benzamide,3-(N-methyl-N-2-hydroxyethyl)benzamide,3-(N-methyl-N-phenyl)benzamide,3-(N-4-acetylpiperaziny-1-yl)benzamide,3-(N-3-methoxypropyl)benzamide, 2-(6-carboxy)pyridine,3-(N-3-hydroxy-4-methoxyphenyl)benzamide,3-(N-3-fluoro-4-methoxyphenyl)benzamide,3-(N-2,3-dimethoxyphenyl)benzamide, 3-(N-3-dimethoxyphenyl)benzamide,3-(N-5-trifluormethyl-1,3,4-thiadiazol-2-yl)benzamide,3-(N-5-methyl-1,3,4-thiadiazol-2-yl)benzamide,3-(N-5-chlorobenzoxazol-2-yl)benzamide, 3-(N-3-benzonitrile)benzamide,3-(N-4-methoxypyrid-3-yl)benzamide, 5-(1,4-benzodioxane),4-(1,3-benzodioxole).
 11. The compound as defined in claim 1 having thestructure:

Chiral (S)

Chiral (S)

Chiral (S)

Chiral (S)

Chiral (S)

Chiral (S)

Chiral (S)

Chiral (S)

Chiral (S)

Chiral (S)

Chiral (S)

Chiral (S)

Chiral (R)

Chiral (R)

Chiral (R)

Chiral (R)

Chiral (R)

Chiral (R)

Chiral (R)


12. The compound as defined in claim 1 having the structure:

Chiral (R)

Chiral (R)

Chiral (R)

Chiral (R)

Chiral (R)

Chiral (R)


13. A compound having the structure:

or an alkyl ester thereof, where R is CH₃, C₂H₅; R^(a) is nitro, cyano,Cl, Br, CH3, —COOCH3, formyl and R^(b) is H; R^(b) is nitro, cyano, Cl,Br, CH3, —COOCH3, formyl and R^(a) is H; or a compound having thestructure:

where X₉ is S or NH; X is:


14. The compound as defined in claim 1 having the structure

where R is CH₃, C₂H₅ or 2-hydroxyethyl, and Rb is H, CN, NO₂, halogen,alkyl or amino; Xb is H, arylalkoxycarbonyl, arylalkylaminocarbonyl,alkoxyalkylaminocarbonyl, heteroarylcarbonyl, aryl,alkoxyalkylamidocarbonyl, arylaminocarbonyl, heteroarylaminocarbonyl,arylaminocarbonylaryl or heteroaryl; provided that where Xb is H, then Ris C₂H₅ or 2-hydroxymethyl or Rb is CN or NO₂.
 15. The compound asdefined in claim 14 having the structure


16. The compound as defined in claim 1 having the structure

where R is CH₃, C₂H₅ or 2-hydroxyethyl, Rb is H, CN, NO₂, halogen, alkylor amino; and Xc is aryl, quinolinyl or isoquinolinyl.
 17. The compoundas defined in claim 16 having the structure


18. A method for preventing, inhibiting onset of or treating aGR-associated disease which is associated with the expression product ofa gene whose transcription is stimulated or repressed by glucocorticoidreceptors, or a method for preventing inhibiting onset of or treating adisease associated with AP-1 induced transcription, or a method forpreventing, inhibiting onset of or treating a disease associated withAP-1 dependent gene expression, that is a disease associated with theexpression of a gene under the regulatory control of AP-1, whichcomprises administering to a patient in need of treatment atherapeutically effective amount of a compound as defined in claim 1.19. The method as defined in claim 18 wherein the GR-associated diseaseis an inflammatory or immune associated disease or disorder which is anendocrine disorder, rheumatic disorder, collagen disease, dermatologicdisease, allergic disease, ophthalmic disease, respiratory disease,hematologic disease, gastrointestinal disease, inflammatory disease,autoimmune disease, neoplastic disease and metabolic disease.
 20. Themethod as defined in claim 19 wherein the inflammatory or immuneassociated disease or disorder is transplant rejection of kidney, liver,heart, lung, pancreas, bone marrow, cornea, small bowel, skinallografts, skin homografts, heart valve xenograft, serum sickness, andgraft vs. host disease, rheumatoid arthritis, psoriatic arthritis,multiple sclerosis, Type I and Type II diabetes, juvenile diabetes,obesity, asthma, inflammatory bowel disease, Crohn's disease, ulcerativecolitis, pyoderma gangrenum, systemic lupus erythematosis, myastheniagravis, psoriasis, dermatitis, dermatomyositis; eczema, seborrhoea,pulmonary inflammation, eye uveitis, hepatitis, Grave's disease,Hashimoto's thyroiditis, autoimmune thyroiditis, Behcet's or Sjorgen'ssyndrome, pernicious or immunohaemolytic anaemia, atherosclerosis,Addison's disease, idiopathic adrenal insufficiency, autoimmunepolyglandular disease, glomerulonephritis, scleroderma, morphea, lichenplanus, viteligo, alopecia areata, autoimmune alopecia, autoimmunehypopituatarism, Guillain-Barre syndrome, and alveolitis; contacthypersensitivity, delayed-type hypersensitivity, contact dermatitis,uticaria, skin allergies, respiratory allergies, hayfever, allergicrhinitis and gluten-sensitive enteropathy, osteoarthritis, acutepancreatis, chronic pancreatitis, acute respiratory distress syndrome,Sezary's syndrome, restenosis, stenosis and artherosclerosis, congenitaladrenal hyperplasia, nonsuppurative thyroiditis, hypercalcemiaassociated with cancer, juvenile rheumatoid arthritis, Ankylosingspondylitis, acute and subacute bursitis, acute nonspecifictenosynovitis, acute gouty arthritis, post-traumatic osteroarthritis,synovitis of osteoarthritis, epicondylitis, acute rheumatic carditis,pemphigus, bullous dermatitis herpetitformis, severe erythemamultiforme, exfoliative dermatitis, psoriasis, seborrheic dermatitis,seasonal or perennial allergic rhinitis, bronchial asthma, contactdermatitis, atopic dermatitis, drug hypersensitivity reactions, allergicconjuncivitis, keratitis, herpes zoster ophthalmicus, iritis andiridocyclitis, chorioretinitis, optic neuritis, symptomatic sarcoidosis,fulminating or disseminated pulmonary tuberculosis chemotherapy,idiopathic thrombocytopenic purpura in adults, secondarythrombocytopenia in adults, acquired (autoimmune) hemolytic anemia,leukemias and lymphomas in adults, acute leukemia of childhood,ulcerative colitis, regional enteritis, Crohn's disease, Sjogren'ssyndrome, autoimmune vasculitis, multiple sclerosis, myasthenia gravis,sepsis, and chronic obstructive pulmonary disease.
 21. A pharmaceuticalcomposition comprising a compound as defined in claim 1 and apharmaceutically acceptable carrier therefor.
 22. A pharmaceuticalcombination comprising a compound as defined in claim 1 and animmunosuppressant, an anticancer agent, an anti-viral agent, ananti-inflammatory agent, an anti-fungal agent, an anti-biotic, ananti-vascular hyperproliferation agent, an anti-depressant agent, alipid-lowering agent, a lipid modulating agent, an antidiabetic agent,an anti-obesity agent, an antihypertensive agent, a platelet aggregationinhibitor, and/or an antiosteoporosis agent, wherein the antidiabeticagent is 1, 2, 3 or more of a biguamide, a sulfonyl urea, a glucosidaseinhibitor, a PPAR γ agonist, a PPAR α/γ dual agonist, an SGLT2inhibitor, a DP4 inhibitor, an aP2 inhibitor, an insulin sensitizer, aglucagon-like peptide-1 (GLP-1), insulin and/or a meglitinide, whereinthe anti-obesity agent is a beta 3 adrenergic agonist, a lipaseinhibitor, a serotonin (and dopamine) reuptake inhibitor, a thyroidreceptor agonist, an aP2 inhibitor and/or an anorectic agent, whereinthe lipid lowering agent is an MTP inhibitor, an HMG CoA reductaseinhibitor, a squalene synthetase inhibitor, a fibric acid derivative, anupregulator of LDL receptor activity, a lipoxygenase inhibitor, or anACAT inhibitor, wherein the antihypertensive agent is an ACE inhibitor,angiotensin II receptor antagonist, NEP/ACE inhibitor, calcium channelblocker and/or β-adrenergic blocker.
 23. The combination as defined inclaim 22 wherein the antidiabetic agent is 1, 2, 3 or more of metformin,glyburide, glimepiride, glipyride, glipizide, chlorpropamide,gliclazide, acarbose, miglitol, pioglitazone, troglitazone,rosiglitazone, insulin, G1-262570, isaglitazone, JTT-501, NN-2344,L895645, YM-440, R-119702, AJ9677, repaglinide, nateglinide, KAD1129,AR-HO39242, GW-409544, KRP297, AC2993, LY315902, P32/98 and/orNVP-DPP-728A, wherein the anti-obesity agent is orlistat, ATL-962,AJ9677, L750355, CP331648, sibutramine, topiramate, axokine,dexamphetamine, phentermine, phenylpropanolamine, and/or mazindol,wherein the lipid lowering agent is pravastatin, lovastatin,simvastatin, atorvastatin, cerivastatin, fluvastatin, itavastatin,visastatin, fenofibrate, gemfibrozil, clofibrate, avasimibe, TS-962,MD-700, cholestagel, niacin and/or LY295427, wherein theantihypertensive agent is an ACE inhibitor which is captopril,fosinopril, enalapril, lisinopril, quinapril, benazepril, fentiapril,ramipril or moexipril; an NEP/ACE inhibitor which is omapatrilat,[S[(R*,R*)]-hexahydro-6-[(2-mercapto-1-oxo-3-phenylpropyl)amino]-2,2-dimethyl-7-oxo-1H-azepine-1-aceticacid (gemopatrilat) or CGS 30440; an angiotensin II receptor antagonistwhich is irbesartan, losartan or valsartan; amlodipine besylate,prazosin HCl, verapamil, nifedipine, nadolol, propranolol, carvedilol,or clonidine HCl, wherein the platelet aggregation inhibitor is aspirin,clopidogrel, ticlopidine, dipyridamole or ifetroban; theimmunosuppressant is a cyclosporin, mycophenolate, interferon-beta,deoxyspergolin, FK-506 or Ant.-IL-2; the anti-cancer agent isazathiprine, 5-fluorouracel, cyclophosphamide, cisplatin, methotrexate,thiotepa, or carboplatin; the anti-viral agent is abacavir, aciclovir,ganciclovir, zidanocin, or vidarabine; the antiinflammatory drug isibuprofen, celecoxib, rofecoxib, aspirin, naproxen, ketoprofen,diclofenac sodium, indomethacin, piroxicam, prednisone, dexamethasone,hydrocortisone, or triamcinolone diacetate.
 24. A method for preparing acompound having the structure:

including all stereoisomers thereof, or a prodrug ester thereof, or apharmaceutically acceptable salt thereof, wherein R is hydrogen, alkyl,alkenyl, alkynyl, alkoxy, aryl, arylalkyl, aryloxy, heteroaryl,cycloheteroalkyl, heteroarylalkyl, cycloheteroalkylalkyl, cycloalkyl,cycloalkylalkyl, cyanoalkyl, aminoalkyl, hydroxyalkyl, aryloxyalkyl, orhydroxyaryl; R^(a) is hydrogen, alkyl, alkenyl, alkynyl, alkoxy, aryl,aryloxy, heteroaryl, cycloheteroalkyl, heteroarylalkyl,cycloheteroalkylalkyl, cyano, halogen, heteroarylaminocarboyl,cycloheteroalkylcarbonyl, cyanoalkyl, alkylaminoalkyl, hydroxyalkyl,hydroxyaryl, aryloxyalkyl, nitro, amino, CHO, CO₂ alkyl, CONR^(e)R^(f),CH₂NR^(g)R^(h), CO₂H, CH₂OH, CH₂NRH^(g), NHCH₂R^(g), NHCHR^(g)R^(h),NHCOR^(e), NHCONR^(e)R^(f) or NHSO₂R^(e); R^(b) is hydrogen, alkyl,alkenyl, alkynyl, alkoxy, aryl, aryloxy, heteroaryl, cycloheteroalkyl,heteroarylalkyl, cycloheteroalkylalkyl, cyano, halogen,heteroarylaminocarbonyl, cycloheteroalkylcarbonyl, cyanoalkyl,alkylaminoalkyl, hydroxyalkyl, nitro, amino, CHO, CO₂ alkyl,hydroxyaryl, aryloxyalkyl, CONR^(i)R^(j), CH₂NR^(k)R^(l), CO₂H, CH₂OH,CH₂NHR^(k), NHCH₂R^(k), NHCHR^(k)R^(l), NHCOR^(i), NHCONR^(i)R^(l) orNHSO₂R^(i); where R^(e) and R^(f) are the same or different and areindependently selected hydrogen, aryl, alkyl, alkenyl, alkynyl, alkoxy,amino, alkoxyalkyl, alkylaminoalkyl, dialkylaminoalkyl, heteroaryl,cycloheteroalkyl, heteroarylalkyl, cycloheteroalkylalkyl, cycloalkyl, orcycloalkylalkyl, and R^(e) and R^(f) can be taken together with thenitrogen to which they are attached to form a 5-, 6- or 7-memberedheteroaryl or cycloheteroalkyl ring which contains 1, 2 or 3 heteroatoms which can be N, or S; R^(g) and R^(h) are the same or differentand are independently selected hydrogen, aryl, alkyl, alkenyl, alkynyl,alkoxy, amino, alkoxyalkyl, alkylaminoalkyl, dialkylaminoalkyl,heteroaryl, cycloheteroalkyl, heteroarylalkyl, cycloheteroalkylalkyl,cycloalkyl, or cycloalkylalkyl, and R^(g) and R^(h) can be takentogether with the nitrogen to which they are attached to form a 5-, 6-or 7-membered heteroaryl ring or cycloheteroalkyl ring which contains 1,2 or 3 hetero atoms which can be N, O or S; R^(i) and R^(j) are the sameor different and are independently selected hydrogen, aryl, alkyl,alkenyl, alkynyl, alkoxy, amino, alkoxyalkyl, alkylaminoalkyl,dialkylaminoalkyl, heteroaryl, cycloheteroalkyl, heteroarylalkyl,cycloheteroalkylalkyl, cycloalkyl, or cycloalkylalkyl, and R^(i) andR^(j) can be taken together with the nitrogen to which they are attachedto form a 5-, 6-or 7-membered heteroaryl ring or cycloheteroalkyl ringwhich contains 1, 2 or 3 hetero atoms which can be N, O or S; R^(k) andR^(l) are the same or different and are independently selected hydrogen,aryl, alkyl, alkenyl, alkynyl, alkoxy, amino, alkoxyalkyl,alkylaminoalkyl, dialkylaminoalkyl, heteroaryl, cycloheteroalkyl,heteroarylalkyl, cycloheteroalkylalkyl, cycloalkyl, or cycloalkylalkyl,and R^(k) and R^(l) can be taken together with the nitrogen to whichthey are attached to form a 5-, 6- or 7-membered heteroaryl ring orcycloheteroalkyl ring which contains 1, 2 or 3 hetero atoms which can beN, O or S; R^(c) and R^(d) are the same or different and areindependently selected from hydrogen, alkyl, alkenyl, alkynyl, alkoxy,aryl, hydroxy, aryloxy, heteroaryl, cycloheteroalkyl, heteroarylalkyl,cycloheteroalkylalkyl, hydroxyaryl, or aryloxyalkyl; R^(c) and R^(d) canbe optionally taken together with the carbon to which they are attachedto form a 3- to 7-membered ring which may optionally include an O atomor an N atom; R¹ and R² are the same or different and are independentlyselected from hydrogen, alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl,cycloalkylalkyl, aryl, heteroaryl, heteroarylalkyl, cycloheteroalkyl,cycloalkenyl, monoalkylaminoalkyl, dialkylaminoalkyl,cycloheteroalkylalkyl, hydroxyaryl, aryloxyalkyl, alkoxyalkyl orhydroxyalkyl; the A ring represents an unsaturated 6-memberedcarbocyclic or heterocyclic ring which is a fused phenyl or pyridyl; andthe B ring represents an unsaturated 6-membered carbocyclic orheterocyclic ring which is fused phenyl or pyridyl; With the followingprovisos: provided that where (a) R is CH₃ or H and R^(a), R^(b), R^(c)and R^(d) are each hydrogen, or (b) R^(a) and R^(b) are each hydrogenand one of R^(c) and R^(d) is alkyl, then (1) at least one of R¹ and R²is heteroaryl, heteroarylalkyl, cycloheteroalkyl orcycloheteroalkylalkyl, but where the heteroaryl is unsubstituted

unsubstituted

or the heteroarylalkyl is unsubstituted

unsubstituted

then the other of R¹ and R² is other than hydrogen, and/or the A ringincludes a hetero atom and/or the B ring includes a hetero atom; or (2)where one of R¹ and R² is phenyl which is substituted with alkyl,hydroxy, halo, C₁—C₂-alkoxycarbonyl or nitro, then (a) the phenyl mustbe substituted with at least one other group other than hydrogen, alkyl,hydroxy, halo, C₁,—C₂-alkoxycarbonyl or nitro, except that the phenylmay be substituted with two or more halo atoms, and/or two or morehydroxy groups and/or (b) the other of R¹ and R² is other than hydrogenand/or (c) the A ring includes a hetero atom and/or the B ring includesa hetero atom; (3) where one of R¹ and R² is phenyl substituted withC₁-C₂ alkoxy, the phenyl cannot be substituted with a second C₁-C₂alkoxy or the other of R¹ and R² is other than hydrogen; or (4) where atleast one of R¹ and R² is hydrogen, unsubstituted alkyl, alkenyl,cycloalkyl, alkylcycloalkyl, cycloalkenyl, alkylcycloalkenyl,alkylphenyl, monoalkylaminoalkyl, dialkylaminoalkyl, arylalkyl, aryl,alkoxyalkyl or hydroxyalkyl then (a) the other of R¹ and R² is otherthan hydrogen, unsubstituted alkyl, alkenyl, cycloaklyl,alkylcycloalkyl, cycloalkenyl, alkylcycloalkenyl, alkylphenyl,monoalkylaminoalkyl, dialkylaminoalkyl, arylalkyl, aryl, alkoxyalkyl orhydroxyalkyl and/or (b) at least one of R^(a), R^(b), R^(c) and/or R^(d)is other than hydrogen and/or (c) R is other than hydrogen or C₁-C₂alkyl and/or (d) the A ring includes a hetero atom and/or the B ringincludes a hetero atom; which comprises treating a compound of thestructure

with an unsaturated compound of the structure

to form the intermediate

where Z¹ is CO₂H or CO₂ alkyl, reacting the above intermediate with anamine of the structure HNR¹R² to form a compound of the structure


25. A method for preparing an amide having the structure:

including all stereoisomers thereof, or a prodrug ester thereof, or apharmaceutically acceptable salt thereof, wherein R is alkyl, alkenyl,alkynyl, alkoxy, aryl, arylalkyl, aryloxy, heteroaryl, cycloheteroalkyl,heteroarylalkyl, cycloheteroalkylalkyl, cycloalkyl, cycloalkylalkyl,cyanoalkyl, aminoalkyl, hydroxyalkyl, aryloxyalkyl, or hydroxyaryl;R^(a) is hydrogen, alkyl, alkenyl, alkynyl, alkoxy, aryl, aryloxy,heteroaryl, cycloheteroalkyl, heteroarylalkyl, cycloheteroalkylalkyl,cyano, halogen, heteroarylaminocarboyl, cycloheteroalkylcarbonyl,cyanoalkyl, alkylaminoalkyl, hydroxyalkyl, hydroxyaryl, aryloxyalkyl,nitro, amino, CHO, CO₂ alkyl, CONR^(e)R^(f), CH₂NR^(g)R^(h),CO₂H, CH₂OH,CH₂NRH^(g), NHCH₂R^(g), NHCHR^(g)R^(h), NHCOR^(e), NHCONR^(e)R^(f) orNHSO₂R^(e); R^(b) is hydrogen, alkyl, alkenyl, alkynyl, alkoxy, aryl,aryloxy, heteroaryl, cycloheteroalkyl, heteroarylalkyl,cycloheteroalkylalkyl, cyano, halogen, heteroarylaminocarbonyl,cycloheteroalkylcarbonyl, cyanoalkyl, alkylaminoalkyl, hydroxyalkyl,nitro, amino, CHO, CO₂ alkyl, hydroxyaryl, aryloxyalkyl, CONR^(i)R^(f),CH₂NR^(k)R^(l), CO₂H, CH₂OH, CH₂NHR^(k), NHCH₂R^(k), NHCHR^(k)R^(l),NHCOR^(i), NHCONR^(i)R^(j) or NHSO₂R^(i); where R^(e) and R^(f) are thesame or different and are independently selected hydrogen, aryl, alkyl,alkenyl, alkynyl, alkoxy, amino, alkoxyalkyl, alkylaminoalkyl,dialkylaminoalkyl, heteroaryl, cycloheteroalkyl, heteroarylalkyl,cycloheteroalkylalkyl, cycloalkyl, or cycloalkylalkyl, and R^(e) andR^(f) can be taken together with the nitrogen to which they are attachedto form a 5-, 6- or 7-membered heteroaryl or cycloheteroalkyl ring whichcontains 1, 2 or 3 hetero atoms which can be N, O or S; R^(g) and R^(h)are the same or different and are independently selected hydrogen, aryl,alkyl, alkenyl, alkynyl, alkoxy, amino, alkoxyalkyl, alkylaminoalkyl,dialkylaminoalkyl, heteroaryl, cycloheteroalkyl, heteroarylalkyl,cycloheteroalkylalkyl, cycloalkyl, or cycloalkylalkyl, and R^(g) andR^(h) can be taken together with the nitrogen to which they are attachedto form a 5-, 6- or 7-membered heteroaryl ring or cycloheteroalkyl ringwhich contains 1, 2 or 3 hetero atoms which can be N, O or S; R^(i) andR^(j) are the same or different and are independently selected hydrogen,aryl, alkyl, alkenyl, alkynyl, alkoxy, amino, alkoxyalkyl,alkylaminoalkyl, dialkylaminoalkyl, heteroaryl, cycloheteroalkyl,heteroarylalkyl, cycloheteroalkylalkyl, cycloalkyl, or cycloalkylalkyl,and R^(i) and R^(j) can be taken together with the nitrogen to whichthey are attached to form a 5-, 6-or 7-membered heteroaryl ring orcycloheteroalkyl ring which contains 1, 2 or 3 hetero atoms which can beN, O or S; R^(k) and R^(l) are the same or different and areindependently selected hydrogen, aryl, alkyl, alkenyl, alkynyl, alkoxy,amino, alkoxyalkyl, alkylaminoalkyl, dialkylaminoalkyl, heteroaryl,cycloheteroalkyl, heteroarylalkyl, cycloheteroalkylalkyl, cycloalkyl, orcycloalkylalkyl, and R^(k) and R^(l) can be taken together with thenitrogen to which they are attached to form a 5-, 6- or 7-memberedheteroaryl ring or cycloheteroalkyl ring which contains 1, 2 or 3 heteroatoms which can be N, O or S; R^(c) and R^(d) are the same or differentand are independently selected from hydrogen, alkyl, alkenyl, alkynyl,alkoxy, aryl, hydroxy, aryloxy, heteroaryl, cycloheteroalkyl,heteroarylalkyl, cycloheteroalkylalkyl, hydroxyaryl, or aryloxyalkyl;R^(c) and R^(d) can be optionally taken together with the carbon towhich they are attached to form a 3- to 7-membered ring which mayoptionally include an O atom or an N atom; R¹ and R² are the same ordifferent and are independently selected from hydrogen, alkyl, alkenyl,alkynyl, alkoxy, cycloalkyl, cycloalkylalkyl, aryl, heteroaryl,heteroarylalkyl, cycloheteroalkyl, cycloalkenyl, monoalkylaminoalkyl,dialkylaminoalkyl, cycloheteroalkylalkyl, hydroxyaryl, aryloxyalkyl,alkoxyalkyl or hydroxyalkyl; the A ring represents an unsaturated6-membered carbocyclic or heterocyclic ring which is a fused phenyl orpyridyl; and the B ring represents an unsaturated 6-membered carbocyclicor heterocyclic ring which is fused phenyl or pyridyl; with thefollowing provisos: provided that where (a) R is CH₃ or H and R^(a),R^(b), R^(c) and R^(d) are each hydrogen, or (b) R^(a) and R^(b) areeach hydrogen and one of R^(c) and R^(d) is alkyl, then (1) at least oneof R¹ and R² is heteroaryl, heteroarylalkyl, cycloheteroalkyl orcycloheteroalkylalkyl, but where the heteroaryl is unsubstituted

unsubstituted

or the heteroarylalkyl is unsubstituted

unsubstituted

then the other of R¹ and R² is other than hydrogen, and/or the A ringincludes a hetero atom and/or the B ring includes a hetero atom; or (2)where one of R¹ and R² is phenyl which is substituted with alkyl,hydroxy, halo, C₁—C₂-alkoxycarbonyl or nitro, then (a) the phenyl mustbe substituted with at least one other group other than hydrogen, alkyl,hydroxy, halo, C₁, —C₂-alkoxycarbonyl or nitro, except that the phenylmay be substituted with two or more halo atoms, and/or two or morehydroxy groups and/or (b) the other of R¹ and R² is other than hydrogenand/or (c) the A ring includes a hetero atom and/or the B ring includesa hetero atom; (3) where one of R¹ and R² is phenyl substituted withC₁—C₂ alkoxy, the phenyl cannot be substituted with a second C₁—C₂alkoxy or the other of R¹ and R² is other than hydrogen; or (4) where atleast one of R¹ and R² is hydrogen, unsubstituted alkyl, alkenyl,cycloalkyl, alkylcycloalkyl, cycloalkenyl, alkylcycloalkenyl,alkylphenyl, monoalkylaminoalkyl, dialkylaminoalkyl, arylalkyl, aryl,alkoxyalkyl or hydroxyalkyl then (a) the other of R¹ and R² is otherthan hydrogen, unsubstituted alkyl, alkenyl, cycloaklyl,alkylcycloalkyl, cycloalkenyl, alkylcycloalkenyl, alkylphenyl,monoalkylaminoalkyl, dialkylaminoalkyl, arylalkyl, aryl, alkoxyalkyl orhydroxyalkyl and/or (b) at least one of R^(a), R^(b), R^(c) and/or R^(d)is other than hydrogen and/or (c) R is other than hydrogen or C₁—C₂alkyl and/or (d) the A ring includes a hetero atom and/or the B ringincludes a hetero atom; which comprises treating a compound of thestructure

where R is H, with a base and a compound of the structure R^(x)-LG whereR^(x) is R other than H and LG is a leaving group to form the compoundof the structure

and treating the above compound with an amine of the structure HNR¹R² toform the corresponding amide.
 26. A method for preparing an amidecompound having the structure:

including all stereoisomers thereof, or a prodrug ester thereof, or apharmaceutically acceptable salt thereof, wherein R is hydrogen, alkyl,alkenyl, alkynyl, alkoxy, aryl, arylalkyl, aryloxy, heteroaryl,cycloheteroalkyl, heteroarylalkyl, cycloheteroalkylalkyl, cycloalkyl,cycloalkylalkyl, cyanoalkyl, aminoalkyl, hydroxyalkyl, aryloxyalkyl, orhydroxyaryl; R^(a) is hydrogen, alkyl, alkenyl, alkynyl, alkoxy, aryl,aryloxy, heteroaryl, cycloheteroalkyl, heteroarylalkyl,cycloheteroalkylalkyl, cyano, halogen, heteroarylaminocarboyl,cycloheteroalkylcarbonyl, cyanoalkyl, alkylaminoalkyl, hydroxyalkyl,hydroxyaryl, aryloxyalkyl, nitro, amino, CHO, CO₂ alkyl, CONR^(e)R^(f),CH₂NR^(g)R^(h), CO₂H, CH₂OH, CH₂NRH^(g), NHCH₂R^(g), NHCHR^(g)R^(h),NHCOR^(e), NHCONR^(e)R^(f) or NHSO₂R^(e); R^(b) is hydrogen, alkyl,alkenyl, alkynyl, alkoxy, aryl, aryloxy, heteroaryl, cycloheteroalkyl,heteroarylalkyl, cycloheteroalkylalkyl, cyano, halogen,heteroarylaminocarbonyl, cycloheteroalkylcarbonyl, cyanoalkyl,alkylaminoalkyl, hydroxyalkyl, nitro, amino, CHO, CO₂ alkyl,hydroxyaryl, aryloxyalkyl, CONR^(i)R^(j), CH₂NR^(k)R^(l), CO₂H, CH₂OH,CH₂NHR^(k), NHCH₂R^(k), NHCHR^(k)R^(l), NHCOR^(i), NHCONR^(i)R^(j) orNHSO₂R^(i); where R^(e) and R^(f) are the same or different and areindependently selected hydrogen, aryl, alkyl, alkenyl, alkynyl, alkoxy,amino, alkoxyalkyl, alkylaminoalkyl, dialkylaminoalkyl, heteroaryl,cycloheteroalkyl, heteroarylalkyl, cycloheteroalkylalkyl, cycloalkyl, orcycloalkylalkyl, and R^(e) and R^(f) can be taken together with thenitrogen to which they are attached to form a 5-, 6- or 7-memberedheteroaryl or cycloheteroalkyl ring which contains 1, 2 or 3 heteroatoms which can be N, O or S; R^(g) and R^(h) are the same or different.and are independently selected hydrogen, aryl, alkyl, alkenyl, alkynyl,alkoxy, amino, alkoxyalkyl, alkylaminoalkyl, dialkylaminoalkyl,heteroaryl, cycloheteroalkyl, heteroarylalkyl, cycloheteroalkylalkyl,cycloalkyl, or cycloalkylalkyl, and R^(g) and R^(h) can be takentogether with the nitrogen to which they are attached to form a 5-, 6-or 7-membered heteroaryl ring or cycloheteroalkyl ring which contains 1,2 or 3 hetero atoms which can be N, O or S; R^(i) and R^(j) are the sameor different and are independently selected hydrogen, aryl, alkyl,alkenyl, alkynyl, alkoxy, amino, alkoxyalkyl, alkylaminoalkyl,dialkylaminoalkyl, heteroaryl, cycloheteroalkyl, heteroarylalkyl,cycloheteroalkylalkyl, cycloalkyl, or cycloalkylalkyl, and R^(i) andR^(j) can be taken together with the nitrogen to which they are attachedto form a 5-, 6-or 7-membered heteroaryl ring or cycloheteroalkyl ringwhich contains 1, 2 or 3 hetero atoms which can be N, O or S; R^(k) andR^(l) are the same or different and are independently selected hydrogen,aryl, alkyl, alkenyl, alkynyl, alkoxy, amino, alkoxyalkyl,alkylaminoalkyl, dialkylaminoalkyl, heteroaryl, cycloheteroalkyl,heteroarylalkyl, cycloheteroalkylalkyl, cycloalkyl, or cycloalkylalkyl,and R^(k) and R^(l) can be taken together with the nitrogen to whichthey are attached to form a 5-, 6- or 7-membered heteroaryl ring orcycloheteroalkyl ring which contains 1, 2 or 3 hetero atoms which can beN, O or S; R^(c) and R^(d) are the same or different and areindependently selected from hydrogen, alkyl, alkenyl, alkynyl, alkoxy,aryl, hydroxy, aryloxy, heteroaryl, cycloheteroalkyl, heteroarylalkyl,cycloheteroalkylalkyl, hydroxyaryl, or aryloxyalkyl; R^(c) and R^(d) canbe optionally taken together with the carbon to which they are attachedto form a 3- to 7-membered ring which may optionally include an O atomor an N atom; R^(1a) and R^(2a) are the same or different and areindependently selected from alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl,cycloalkylalkyl, aryl, heteroaryl, heteroarylalkyl, cycloheteroalkyl,cycloalkenyl, monoalkylaminoalkyl, dialkylaminoalkyl,cycloheteroalkylalkyl, hydroxyaryl, aryloxyalkyl, alkoxyalkyl orhydroxyalkyl; the A ring represents an unsaturated 6-memberedcarbocyclic or heterocyclic ring; and the B ring represents anunsaturated 6-membered carbocyclic or heterocyclic ring; which comprisestreating a compound

where R² is H and R^(1a) is R¹ other than H; with an amine of thestructure HNR^(1a)R² treating a compound of the structure

where R² is H, and R^(1a) is R¹ other than H, with a base and a compoundof the structure R^(2a)-LG where LG is a leaving group, to form thecompound of the structure


27. A method for preparing an amine compound having the structure:

including all stereoisomers thereof, or a prodrug ester thereof, or apharmaceutically acceptable salt thereof, wherein R is hydrogen, alkyl,alkenyl, alkynyl, alkoxy, aryl, arylalkyl, aryloxy, heteroaryl,cycloheteroalkyl, heteroarylalkyl, cycloheteroalkylalkyl, cycloalkyl,cycloalkylalkyl, cyanoalkyl, aminoalkyl, hydroxyalkyl, aryloxyalkyl, orhydroxyaryl; R^(a) is hydrogen, alkyl, alkenyl, alkynyl, alkoxy, aryl,aryloxy, heteroaryl, cycloheteroalkyl, heteroarylalkyl,cycloheteroalkylalkyl, cyano, halogen, heteroarylaminocarboyl,cycloheteroalkylcarbonyl, cyanoalkyl, alkylaminoalkyl, hydroxyalkyl,hydroxyaryl, aryloxyalkyl, nitro, amino, CHO, CO₂ alkyl, CONR^(e)R^(f),CH2 NR^(g)R^(h), CO₂H, CH₂OH, CH2NRH^(g), NHCH₂R^(g), NHCHR^(g)R^(h),NHCOR^(e), NHCONR^(e)R^(f) or NHSO₂R^(e); R^(b) is hydrogen, alkyl,alkenyl, alkynyl, alkoxy, aryl, aryloxy, heteroaryl, cycloheteroalkyl,heteroarylalkyl, cycloheteroalkylalkyl, cyano, halogen,heteroarylaminocarbonyl, cycloheteroalkylcarbonyl, cyanoalkyl,alkylaminoalkyl, hydroxyalkyl, nitro, amino, CHO, CO₂ alkyl,hydroxyaryl, aryloxyalkyl, CONR^(i)R^(j), CH₂NR^(k)R^(l), CO₂H, CH₂OH,CH₂NHR^(k), NHCH₂R^(k), NHCHR^(k)R^(l), NHCOR^(i), NHCONR^(i)R^(j) orNHSO₂R^(i); where R^(e) and R^(f) are the same or different and areindependently selected hydrogen, aryl, alkyl, alkenyl, alkynyl, alkoxy,amino, alkoxyalkyl, alkylaminoalkyl, dialkylaminoalkyl, heteroaryl,cycloheteroalkyl, heteroarylalkyl, cycloheteroalkylalkyl, cycloalkyl, orcycloalkylalkyl, and R^(e) and R^(f) can be taken together with thenitrogen to which they are attached to form a 5-, 6- or 7-memberedheteroaryl or cycloheteroalkyl ring which contains 1, 2 or 3 heteroatoms which can be N, O or S; R^(g) and R^(h) are the same or differentand are independently selected hydrogen, aryl, alkyl, alkenyl, alkynyl,alkoxy, amino, alkoxyalkyl, alkylaminoalkyl, dialkylaminoalkyl,heteroaryl, cycloheteroalkyl, heteroarylalkyl, cycloheteroalkylalkyl,cycloalkyl, or cycloalkylalkyl, and R^(g) and R^(h) can be takentogether with the nitrogen to which they are attached to form a 5-, 6-or 7-membered heteroaryl ring or cycloheteroalkyl ring which contains 1,2 or 3 hetero atoms which can be N, O or S; R^(i) and R^(j) are the sameor different and are independently selected hydrogen, aryl, alkyl,alkenyl, alkynyl, alkoxy, amino, alkoxyalkyl, alkylaminoalkyl,dialkylaminoalkyl, heteroaryl, cycloheteroalkyl, heteroarylalkyl,cycloheteroalkylalkyl, cycloalkyl, or cycloalkylalkyl, and R^(i) andR^(j) can be taken together with the nitrogen to which they are attachedto form a 5-, 6-or 7-membered heteroaryl ring or cycloheteroalkyl ringwhich contains 1, 2 or 3 hetero atoms which can be N, O or S; R^(k) andR^(l) are the same or different and are independently selected hydrogen,aryl, alkyl, alkenyl, alkynyl, alkoxy, amino, alkoxyalkyl,alkylaminoalkyl, dialkylaminoalkyl, heteroaryl, cycloheteroalkyl,heteroarylalkyl, cycloheteroalkylalkyl, cycloalkyl, or cycloalkylalkyl,and R^(k) and R^(l) can be taken together with the nitrogen to whichthey are attached to form a 5-, 6- or 7-membered heteroaryl ring orcycloheteroalkyl ring which contains 1, 2 or 3 hetero atoms which can beN, O or S; R^(c) and R^(d) are the same or different and areindependently selected from hydrogen, alkyl, alkenyl, alkynyl, alkoxy,aryl, hydroxy, aryloxy, heteroaryl, cycloheteroalkyl, heteroarylalkyl,cycloheteroalkylalkyl, hydroxyaryl, or aryloxyalkyl; R^(c) and R^(d) canbe optionally taken together with the carbon to which they are attachedto form a 3- to 7-membered ring which may optionally include an O atomor an N atom; R¹ and R² are the same or different and are independentlyselected from hydrogen, alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl,cycloalkylalkyl, aryl, heteroaryl, heteroarylalkyl, cycloheteroalkyl,cycloalkenyl, monoalkylaminoalkyl, dialkylaminoalkyl,cycloheteroalkylalkyl, hydroxyaryl, aryloxyalkyl, alkoxyalkyl orhydroxyalkyl; the A ring represents a saturated, partially saturated orunsaturated 6-membered carbocyclic or heterocyclic ring; and the B ringrepresents a saturated, partially saturated or unsaturated 6-memberedcarbocyclic or heterocyclic ring; provided that where least one of R¹and R² is hydrogen, alkyl, alkenyl, cycloalkyl, alkylcycloalkyl, phenyl,alkylphenyl, phenylalkyl, monoalkylaminoalkyl, dialkylaminoalkyl,arylalkyl, aryl, alkoxyalkyl, hydroxyalkyl, heteroaryl which ispyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl or imidazolinyl, orcycloheteroalkyl which is 4,5-dihydro-imidazol-2-yl, piperidinyl orpiperazinyl, then (a) the other of R¹ and R² is other than hydrogen,alkyl, alkenyl, cycloalkyl, alkylcycloalkyl, phenyl, alkylphenyl,phenylalkyl, monoalkylaminoalkyl, dialkylaminoalkyl, arylalkyl, aryl,alkoxyalkyl, or hydroxyalkyl, and/or (b) at least one of R^(a), R^(b),R^(c) and/or R^(d) is other than hydrogen or C₁₋₂ alkyl, and/or (c) R isother than hydrogen or C₁—C₂ alkyl and/or (d) the A ring includes ahetero atom and/or the B ring includes a hetero atom, and/or (e) one ofR^(c) and R^(d) is other than hydroxyalkyl, which comprises treating anamide compound of the structure

as defined in claim 1 with a reducing agent to form the correspondingamine compound.
 28. The method as defined in claim 27 wherein thereducing agent is lithium aluminum hydride.
 29. A method for preparing acompound as defined in claim 1 where A, B, Z, R, R^(a), R^(b), R^(c) orR^(d) contains a hydroxyaryl group, which comprises providing a compoundof the structure

where one or more of A, B, Z, R, R^(a), R^(b), R^(c) or R^(d) containsaryl-Oalkyl, and reacting the above compound with a dealkylating agentto form a phenol of the structure

where the corresponding A, B, Z, R, R^(a), R^(b), R^(c) or R^(d)contains aryl-OH.
 30. The method as defined in claim 29 wherein thedealkylating agent is boron tribromide or sodium methyl sulfide.
 31. Amethod for preparing a compound as defined in claim 1 wherein R^(a) orR^(b) is CH₂OH, CH₂NHR^(a), CH₂NR^(g)R^(h), CH₂NHR^(k) orCH₂NR^(k)R^(l), which comprises providing an aldehyde compound asdefined in claim 1 wherein R^(a) or R^(b) is CHO, and subjecting thealdehyde compound to reduction or reductive amination.
 32. A method forpreparing an amide compound as defined in claim 1 where R^(a) or R^(b)is NHCH₂R^(g), NHCHR^(g)R^(h), NHCH₂R^(k) or NHCHR^(k)R^(l), whichcomprises providing an amine compound as defined in claim 1 where R^(a)or R^(b) is NH₂, and subjecting the amine compound to reductiveamination.
 33. A method for preparing an amide compound as defined inclaim 1 where R^(a) or R^(b) is CONR^(e)R^(f) or CONR^(l)R^(j), whichcomprises providing an acid compound as defined in claim 1 where R^(a)or R^(b) is CO₂H, subjecting the acid to amidation to form thecorresponding amide.
 34. A method for preparing an amine as defined inclaim 1 where R^(a) or R^(b) is NH₂, which comprises providing a nitrocompound as defined in claim 1 where R^(a) or R^(b) is NO₂ andsubjecting the nitro compound to reduction to form the correspondingamine compound.